Safety, Tolerability and Immune Response to LC002, an Experimental Therapeutic Vaccine, in Adults Receiving HAART - Study Results

Study Type:	Interventional
Study Design:	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double Blind (Participant, Care Provider, Investigator); Primary Purpose: Treatment
Condition:	HIV Infections
Interventions:	Biological: LC002 standard vaccination Biological: LC002 high-dose vaccination Biological: LC002 placebo vaccination

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Participants were enrolled from February 2006 to October 2008 in 5 different U.S. sites. Enrollment was done by cohort with each cohort enrolling six participants for LC002 vaccine and 2 participants for its corresponding placebo. Cohorts were enrolled sequentially, with later cohorts receiving higher dose of the LC002 vaccine.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Study participants were HIV-1-infected men and women 18-50 years of age with CD4 count >350 cells/mm^3 and plasma HIV-1 RNA <50 copies/ml (on an ultrasensitive assay) and who were on a stable HAART regimen. One enrolled participant never started study treatment/vaccination.

Reporting Groups

	Description
A: 0.1 mg DNA/Participant Vaccination at Weeks 1, 7, 13	Participants receiving three separate low-dose vaccinations of LC002 (0.1 mg DNA/participant, 0.8 ml total, administered over two skin sites [on the left and right upper back] of 80 cm^2 each, 0.4 ml/site) at weeks 1, 7, and 13.
C: 0.4 mg DNA/Participant Vaccination at Weeks 1, 7, 13	Participants receiving three separate high-dose vaccinations of LC002 (0.4 mg DNA/participant, 3.2 ml total, administered over four skin sites [on the left and right upper back and left and right upper ventral thigh] of 80 cm^2 each, 0.8 ml/site) at weeks 1, 7, and 13.
E: 0.4 mg DNA/Participant Vaccination at Weeks 0,1,6,7,12,13	Participants receiving six separate high-dose vaccinations of LC002 (0.4 mg DNA/participant, 3.2 ml total, administered over four skin sites [on the left and right upper back and left and right upper ventral thigh] of 80 cm^2 each, 0.8 ml/site) at study entry and weeks 1, 6, 7, 12, and 13.
Placebo	All participants receiving vaccinations of LC002 placebo were combined together in this arm/group. This includes those participants in arms B, D and F.

Participant Flow: Overall Study

	A: 0.1 mg DNA/Participant Vaccination at Weeks 1, 7, 13	C: 0.4 mg DNA/Participant Vaccination at Weeks 1, 7, 13	E: 0.4 mg DNA/Participant Vaccination at Weeks 0,1,6,7,12,13	Placebo
STARTED	6	6 ^[1]	6	7
COMPLETED	5	6	6	6
NOT COMPLETED	1	0	0	1
Lost to Follow-up	1	0	0	1

^[1]	7 participants enrolled. One never started study vaccination and was excluded from all analyses.

Baseline Characteristics

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Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups

	Description
A: 0.1 mg DNA/Participant Vaccination at Weeks 1, 7, 13	Participants receiving three separate low-dose vaccinations of LC002 (0.1 mg DNA/participant, 0.8 ml total, administered over two skin sites [on the left and right upper back] of 80 cm^2 each, 0.4 ml/site) at weeks 1, 7, and 13.
C: 0.4 mg DNA/Participant Vaccination at Weeks 1, 7, 13	Participants receiving three separate high-dose vaccinations of LC002 (0.4 mg DNA/participant, 3.2 ml total, administered over four skin sites [on the left and right upper back and left and right upper ventral thigh] of 80 cm^2 each, 0.8 ml/site) at weeks 1, 7, and 13.
E: 0.4 mg DNA/Participant Vaccination at Weeks 0,1,6,7,12,13	Participants receiving six separate high-dose vaccinations of LC002 (0.4 mg DNA/participant, 3.2 ml total, administered over four skin sites [on the left and right upper back and left and right upper ventral thigh] of 80 cm^2 each, 0.8 ml/site) at study entry and weeks 1, 6, 7, 12, and 13.
Placebo	All participants receiving vaccinations of LC002 placebo were combined together in this arm/group. This includes those participants in arms B, D and F.
Total	Total of all reporting groups

Baseline Measures

A: 0.1 mg DNA/Participant Vaccination at Weeks 1, 7, 13

C: 0.4 mg DNA/Participant Vaccination at Weeks 1, 7, 13

E: 0.4 mg DNA/Participant Vaccination at Weeks 0,1,6,7,12,13

Placebo

Total

Overall Participants Analyzed
[Units: Participants]

6

7

25

Age ^[1]
[Units: Years]
Median (Inter-Quartile Range)

44
(32 to 48)

41
(38 to 43)

46
(34 to 47)

34
(30 to 35)

39
(32 to 45)

^[1]	Age (in years) at study entry. Participants who never started study vaccination were excluded.

Age, Customized ^[1]
[Units: Participants]

18-30

1

2

5

31-40

2

1

5

10

41-50

3

4

0

10

^[1]	Age (in years) at study entry. Participants who never started study vaccination were excluded.

Gender ^[1]
[Units: Participants]

Female

1

0

1

2

Male

5

6

23

^[1]	Participants who never started study vaccination were excluded.

Region of Enrollment
[Units: Participants]

United States

6

7

25

Outcome Measures

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1. Primary:

Percent of Participants With Primary Safety Endpoint [ Time Frame: From start of study vaccination to 28 days after the last study vaccination ]

Show Outcome Measure 1

2. Secondary:

Time-averaged Area Under the Curve (AUC) of CD4+ T-cell Count in PBMCs [ Time Frame: From start of study vaccination to week 61 ]

Show Outcome Measure 2

3. Secondary:

Time-averaged AUC of CD8+ T-cell Count in PBMCs [ Time Frame: From start of study vaccination to week 61 ]

Show Outcome Measure 3

4. Secondary:

Time-averaged AUC of the Magnitude of HIV-specific Immune Response, as Determined by Taking the Mean of the Number of Spot-forming Cells/10^6 PBMCs Observed in Each PHPC Assay for IFN-gamma Production for Gag p17, Gag p24, Gag p15 and Tat/Rev. [ Time Frame: From start of study vaccination to week 37 ]

Show Outcome Measure 4

5. Secondary:

Time-averaged AUC of the Magnitude of HIV-specific Immune Response, as Determined by the Number of Spot-forming Cells/10^6 PBMCs Observed in Each PHPC Assay for IFN-gamma Production for Gag p17, Gag p24, Gag p15 and Tat/Rev. [ Time Frame: From start of study vaccination to week 37 ]

Show Outcome Measure 5

6. Secondary:

Time-averaged AUC of the Magnitude of HIV-specific Immune Response, as Determined by Taking the Mean of the Number of Spot-forming Cells/10^6 PBMCs Observed in Each ELISPOT Assay for IFN-gamma Production for Gag p17, Gag p24, Gag p15 and Tat/Rev. [ Time Frame: From start of study vaccination to week 37 ]

Show Outcome Measure 6

7. Secondary:

Time-averaged AUC of the Magnitude of HIV-specific Immune Response, as Determined by the Number of Spot-forming Cells/10^6 PBMCs Observed in Each ELISPOT Assay for IFN-gamma Production for Gag p17, Gag p24, Gag p15 and Tat/Rev. [ Time Frame: From start of study vaccination to week 37 ]

Show Outcome Measure 7

8. Secondary:

Anti-dsDNA Antibody Response [ Time Frame: From start of study vaccination to week 61 ]

Show Outcome Measure 8

9. Secondary:

Time-averaged AUC of T-cell Count of HIV-1-specific CD4+ T-cell Subsets, Based on Flow Cytometry With CFSE Staining to Detect Antigen-specific Lymphocyte Proliferation Responding to p24 Protein, Gag/Pol/Env and Tat/Rev [ Time Frame: From start of study vaccination to week 24 ]

Show Outcome Measure 9

10. Secondary:

Time-averaged AUC of T-cell Count of HIV-1-specific CD4+ T-cell Subsets, Based on Flow Cytometry With CFSE Staining to Detect Antigen-specific Lymphocyte Proliferation Responding to Whole HIV-1 Antigen [ Time Frame: From start of study vaccination to week 24 ]

Show Outcome Measure 10

11. Secondary:

Time-averaged AUC of T-cell Count of HIV-1-specific CD4+ T-cell Subsets, Based on Flow Cytometry With CFSE Staining to Detect Antigen-specific Lymphocyte Proliferation Responding to Anti-CD3 [ Time Frame: From start of study vaccination to week 24 ]

Show Outcome Measure 11

12. Secondary:

Time-averaged AUC of T-cell Percent of HIV-1-specific CD4+ T-cell Subsets, Based on Flow Cytometry With CFSE Staining to Detect Antigen-specific Lymphocyte Proliferation Responding to p24 Protein, Gag/Pol/Env and Tat/Rev. [ Time Frame: From start of study vaccination to week 24 ]

Show Outcome Measure 12

13. Secondary:

Time-averaged AUC of T-cell Percent of HIV-1-specific CD4+ T-cell Subsets, Based on Flow Cytometry With CFSE Staining to Detect Antigen-specific Lymphocyte Proliferation Responding to Whole HIV-1 Antigen [ Time Frame: From start of study vaccination to week 24 ]

Show Outcome Measure 13

14. Secondary:

Time-averaged AUC of T-cell Percent of HIV-1-specific CD4+ T-cell Subsets, Based on Flow Cytometry With CFSE Staining to Detect Antigen-specific Lymphocyte Proliferation Responding to Anti-CD3 [ Time Frame: From start of study vaccination to week 24 ]

Show Outcome Measure 14

15. Secondary:

Time-averaged AUC of T-cell Count of HIV-1-specific CD8+ T-cell Subsets, Based on Flow Cytometry With CFSE Staining to Detect Antigen-specific Lymphocyte Proliferation Responding to p24 Protein, Gag/Pol/Env, Tat/Rev and Whole HIV-1 Antigen. [ Time Frame: From start of study vaccination to week 24 ]

Show Outcome Measure 15

16. Secondary:

Time-averaged AUC of T-cell Count of HIV-1-specific CD8+ T-cell Subsets, Based on Flow Cytometry With CFSE Staining to Detect Antigen-specific Lymphocyte Proliferation Responding to Anti-CD3 [ Time Frame: From start of study vaccination to week 24 ]

Show Outcome Measure 16

17. Secondary:

Time-averaged AUC of T-cell Percent of HIV-1-specific CD8+ T-cell Subsets, Based on Flow Cytometry With CFSE Staining to Detect Antigen-specific Lymphocyte Proliferation Responding to p24 Protein, Gag/Pol/Env, Tat/Rev and Whole HIV-1 Antigen. [ Time Frame: From start of study vaccination to week 24 ]

Show Outcome Measure 17

18. Secondary:

Time-averaged AUC of T-cell Percent of HIV-1-specific CD8+ T-cell Subsets, Based on Flow Cytometry With CFSE Staining to Detect Antigen-specific Lymphocyte Proliferation Responding to Anti-CD3 [ Time Frame: From start of study vaccination to week 24 ]

Show Outcome Measure 18

19. Secondary:

Time-averaged AUC of T-cell Count of HIV-1-specific CD4+ T-cell Subsets, Based on Flow Cytometry to Detect Antigen-specific IFN-gamma-producing Cells Responding to Whole Zn-finger Inactivated Virus Stimulation and Various HIV-1 Peptide Antigens [ Time Frame: From start of study vaccination to week 24 ]

Show Outcome Measure 19

20. Secondary:

Time-averaged AUC of T-cell Percent of HIV-1-specific CD4+ T-cell Subsets, Based on Flow Cytometry to Detect Antigen-specific IFN-gamma-producing Cells Responding to Whole Zn-finger Inactivated Virus Stimulation and Various HIV-1 Peptide Antigens [ Time Frame: From start of study vaccination to week 24 ]

Show Outcome Measure 20

21. Secondary:

Time-averaged AUC of T-cell Count of HIV-1-specific CD8+ T-cell Subsets, Based on Flow Cytometry to Detect Antigen-specific IFN-gamma-producing Cells Responding to Whole Zn-finger Inactivated Virus Stimulation and Various HIV-1 Peptide Antigens [ Time Frame: From start of study vaccination to week 24 ]

Show Outcome Measure 21

22. Secondary:

Time-averaged AUC of T-cell Percent of HIV-1-specific CD8+ T-cell Subsets, Based on Flow Cytometry to Detect Antigen-specific IFN-gamma-producing Cells Responding to Whole Zn-finger Inactivated Virus Stimulation and Various HIV-1 Peptide Antigens [ Time Frame: From start of study vaccination to week 24 ]

Show Outcome Measure 22

23. Secondary:

Time-averaged AUC of T-cell Count of HIV-1-specific CD4+ T-cell Subsets, Based on Flow Cytometry to Detect Antigen-specific IL-2-producing Cells Responding to Whole Zn-finger Inactivated Virus Stimulation and Various HIV-1 Peptide Antigens [ Time Frame: From start of study vaccination to week 24 ]

Show Outcome Measure 23

24. Secondary:

Time-averaged AUC of T-cell Percent of HIV-1-specific CD4+ T-cell Subsets, Based on Flow Cytometry to Detect Antigen-specific IL-2-producing Cells Responding to Whole Zn-finger Inactivated Virus Stimulation and Various HIV-1 Peptide Antigens [ Time Frame: From start of study vaccination to week 24 ]

Show Outcome Measure 24

25. Secondary:

Time-averaged AUC of T-cell Count of HIV-1-specific CD8+ T-cell Subsets, Based on Flow Cytometry to Detect Antigen-specific IL-2-producing Cells Responding to Whole Zn-finger Inactivated Virus Stimulation and Various HIV-1 Peptide Antigens [ Time Frame: From start of study vaccination to week 24 ]

Show Outcome Measure 25

26. Secondary:

Time-averaged AUC of T-cell Percent of HIV-1-specific CD8+ T-cell Subsets, Based on Flow Cytometry to Detect Antigen-specific IL-2-producing Cells Responding to Whole Zn-finger Inactivated Virus Stimulation and Various HIV-1 Peptide Antigens [ Time Frame: From start of study vaccination to week 24 ]

Show Outcome Measure 26

27. Secondary:

Lymphocyte Proliferation Stimulation Index (SI) in Response to Whole HIV-1 Antigen, p24 Antigen, and Pooled HIV-1 Peptide Antigens [ Time Frame: Throughout study ]

Results not yet reported. Anticipated Reporting Date: No text entered.

28. Secondary:

Breadth of HIV-1-specific Immune Response, as Determined by the Number of Overlapping HIV-1 Peptides for Which the ELISPOT Assay for IFN-gamma Production is Observed to Have Five or More Spot-forming Cells/ 10^5 PBMCs [ Time Frame: Throughout study ]

Results not yet reported. Anticipated Reporting Date: No text entered.

Serious Adverse Events

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Other Adverse Events

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Limitations and Caveats

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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
This is a Phase I/II small sample study that was not powered for the secondary efficacy endpoints.

More Information

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Certain Agreements:

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: In accordance with the Clinical Trial Agreement between NIAID (DAIDS) and company collaborators, NIAID (DAIDS) provides companies with a copy of any abstract, press release, or manuscript prior to submission for publication with sufficient time for company review and comment. The publication/other disclosure can be delayed for up to 30 additional business days for manuscripts and five (5) business days for abstracts, to preserve U.S. or foreign patent or other intellectual property rights.

Results Point of Contact:

Name/Title: Clinicaltrials.gov Coordinator
Organization: Center for Biostatistics in AIDS Research, Harvard School of Public Health
phone: (617)432-2829
e-mail: CBAR.ClinicalTrials.Gov@sdac.harvard.edu

Publications of Results:

Natz E, Lisziewicz J. Rational Design of Formulated DNA Vaccines: The DermaVir Approach. In J. Thalhamer, R. Weiss & S. Scheiblhofer (Eds.), Gene Vaccines. In press.

Other Publications:

Lisziewicz J, Trocio J, Xu J, Whitman L, Ryder A, Bakare N, Lewis MG, Wagner W, Pistorio A, Arya S, Lori F. Control of viral rebound through therapeutic immunization with DermaVir. AIDS. 2005 Jan 3;19(1):35-43.

Lori F, Trocio J, Bakare N, Kelly LM, Lisziewicz J. DermaVir, a novel HIV immunisation technology. Vaccine. 2005 Mar 18;23(17-18):2030-4.

Lori F, Weiner DB, Calarota SA, Kelly LM, Lisziewicz J. Cytokine-adjuvanted HIV-DNA vaccination strategies. Springer Semin Immunopathol. 2006 Nov;28(3):231-8. Epub 2006 Oct 20. Review.

Rajcáni J, Mosko T, Rezuchová I. Current developments in viral DNA vaccines: shall they solve the unsolved? Rev Med Virol. 2005 Sep-Oct;15(5):303-25. Review.

Somogyi E, Xu J, Gudics A, Tóth J, Kovács AL, Lori F, Lisziewicz J. A plasmid DNA immunogen expressing fifteen protein antigens and complex virus-like particles (VLP+) mimicking naturally occurring HIV. Vaccine. 2011 Jan 17;29(4):744-53. doi: 10.1016/j.vaccine.2010.11.019. Epub 2010 Nov 23.

Lőrincz O, Tőke ER, Somogyi E, Horkay F, Chandran PL, Douglas JF, Szebeni J, Lisziewicz J. Structure and biological activity of pathogen-like synthetic nanomedicines. Nanomedicine. 2012 May;8(4):497-506. doi: 10.1016/j.nano.2011.07.013. Epub 2011 Aug 10.

Toke ER, Lorincz O, Somogyi E, Lisziewicz J. Rational development of a stable liquid formulation for nanomedicine products. Int J Pharm. 2010 Jun 15;392(1-2):261-7. doi: 10.1016/j.ijpharm.2010.03.048. Epub 2010 Mar 25.

Cristillo AD, Lisziewicz J, He L, Lori F, Galmin L, Trocio JN, Unangst T, Whitman L, Hudacik L, Bakare N, Whitney S, Restrepo S, Suschak J, Ferrari MG, Chung HK, Kalyanaraman VS, Markham P, Pal R. HIV-1 prophylactic vaccine comprised of topical DermaVir prime and protein boost elicits cellular immune responses and controls pathogenic R5 SHIV162P3. Virology. 2007 Sep 15;366(1):197-211. Epub 2007 May 11.

Lisziewicz J, Trocio J, Whitman L, Varga G, Xu J, Bakare N, Erbacher P, Fox C, Woodward R, Markham P, Arya S, Behr JP, Lori F. DermaVir: a novel topical vaccine for HIV/AIDS. J Invest Dermatol. 2005 Jan;124(1):160-9.

Lisziewicz J, Rosenberg E, Lieberman J, Jessen H, Lopalco L, Siliciano R, Walker B, Lori F. Control of HIV despite the discontinuation of antiretroviral therapy. N Engl J Med. 1999 May 27;340(21):1683-4.

Calarota SA, Foli A, Maserati R, Baldanti F, Paolucci S, Young MA, Tsoukas CM, Lisziewicz J, Lori F. HIV-1-specific T cell precursors with high proliferative capacity correlate with low viremia and high CD4 counts in untreated individuals. J Immunol. 2008 May 1;180(9):5907-15.

Gudmundsdotter L, Wahren B, Haller BK, Boberg A, Edbäck U, Bernasconi D, Buttò S, Gaines H, Imami N, Gotch F, Lori F, Lisziewicz J, Sandström E, Hejdeman B. Amplified antigen-specific immune responses in HIV-1 infected individuals in a double blind DNA immunization and therapy interruption trial. Vaccine. 2011 Jul 26;29(33):5558-66. doi: 10.1016/j.vaccine.2011.01.064. Epub 2011 Feb 5.

Responsible Party:	National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:	NCT00270205 History of Changes
Other Study ID Numbers:	A5176 10126 ( Registry Identifier: DAIDS ES ) ACTG A5176
Study First Received:	December 21, 2005
Results First Received:	September 7, 2011
Last Updated:	March 5, 2014