Safety and Immunogenicity of GlaxoSmithKline Biologicals' HPV Vaccine 580299 (Cervarix TM) in HIV Infected Females

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT00586339
First received: December 21, 2007
Last updated: July 19, 2012
Last verified: July 2012
  Purpose

Infection with human papillomavirus (HPV) has been clearly established as the central cause of cervical cancer. The current study is designed to evaluate the safety and immunogenicity of GlaxoSmithKline Biologicals' HPV vaccine 580299 in HIV infected adult females living in the Republic of South Africa. The study is double blinded, randomized for HIV positive subjects and open for HIV negative subjects. The Protocol Posting has been updated in order to comply with the FDA Amendment Act, Sep 2007.


Condition Intervention Phase
HPV-16/18 Infections
Cervical Neoplasia
Biological: Cervarix TM
Biological: Placebo Control
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Prevention
Official Title: Evaluation of the Safety and Immunogenicity of GlaxoSmithKline Biologicals' HPV Vaccine 580299 (Cervarix TM) in Adult Human Immunodeficiency Virus (HIV) Infected Female Subjects

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Number of Subjects Reporting Any Solicited Local Symptoms. [ Time Frame: Within 7 days (Days 0-6) after vaccination. ] [ Designated as safety issue: No ]

    Solicited local symptoms assessed were pain and swelling. Any = incidence of a particular symptom regardless of intensity grade. Solicited adverse events (AEs) = symptom to be recorded as endpoints in the clinical study. The presence/occurrence/intensity of these events was actively solicited from the subject or an observer during a specified post-vaccination follow-up period.

    Solicited local symptoms were assessed as related to the study vaccination.


  • Number of Subjects Reporting Severe (Grade 3) Solicited Local Symptoms. [ Time Frame: Within 7 days (Days 0-6) after vaccination. ] [ Designated as safety issue: No ]
    Grade 3 swelling was greater than 50 millimeter (mm) i.e. >50 mm and grade 3 pain was pain that prevented normal everyday activities.

  • Number of Subjects Reporting Any, Severe (Grade 3) and Related Solicited General Symptoms. [ Time Frame: Within 7 days (Days 0-6) after vaccination. ] [ Designated as safety issue: No ]

    Solicited general symptoms assessed were arthralgia, fatigue, gastrointestinal, headache, myalgia, rash, urticaria and fever (= axillary temperature equal to or above 37.5 degrees Celsius (°C).

    Any = occurrence of any solicited general symptom regardless of their intensity grade or relationship.

    Grade 3 Symptom = symptom that prevented normal activity. Grade 3 Urticaria = Urticaria distributed on at least 4 body areas. Related = symptom assessed by the investigator as causally related to the vaccination.


  • Number of Subjects Reporting Any and Related Unsolicited Symptoms. [ Time Frame: Within 30 days (Days 0-29) after vaccination. ] [ Designated as safety issue: No ]

    Any adverse event (AE) reported in addition to those solicited during the clinical study. Also any "solicited" symptom with onset outside the specified period of follow-up for solicited symptoms was reported as an unsolicited adverse event.

    Related = event assessed by the investigator as causally related to the study vaccination.


  • Number of Subjects Reporting Severe (Grade 3) Unsolicited Symptoms. [ Time Frame: Within 30 days (Days 0-29) after vaccination. ] [ Designated as safety issue: No ]

    Any adverse event (AE) reported in addition to those solicited during the clinical study. Also any "solicited" symptom with onset outside the specified period of follow-up for solicited symptoms was reported as an unsolicited adverse event.

    Grade 3= event that prevented normal activity.


  • Number of Subjects With Medically Significant Conditions. [ Time Frame: Up to Month 7. ] [ Designated as safety issue: No ]

    Medically significant conditions were collected regardless of causal relationship to vaccination and intensity.

    Medically significant conditions were defined as adverse events (AEs) prompting emergency room or physician visits that were not (1) related to common diseases or (2) routine visits for physical examination or vaccination, or serious adverse events (SAEs) that were not related to common diseases.


  • Number of Subjects Reporting Serious Adverse Events (SAEs). [ Time Frame: Up to Month 7. ] [ Designated as safety issue: No ]
    SAEs assessed include medical occurrences that results in death, are life threatening, require hospitalization or prolongation of hospitalization, results in disability/incapacity or are a congenital anomaly/birth defect in the offspring of a study subjects.

  • Number of Subjects With Medically Significant Conditions. [ Time Frame: Up to Month 12. ] [ Designated as safety issue: No ]

    Medically significant conditions were collected regardless of causal relationship to vaccination and intensity.

    Medically significant conditions were defined as adverse events (AEs) prompting emergency room or physician visits that were not (1) related to common diseases or (2) routine visits for physical examination or vaccination, or serious adverse events (SAEs) that were not related to common diseases.


  • Number of Subjects Reporting Serious Adverse Events (SAEs). [ Time Frame: Up to Month 12. ] [ Designated as safety issue: No ]
    SAEs assessed include medical occurrences that results in death, are life threatening, require hospitalization or prolongation of hospitalization, results in disability/incapacity or are a congenital anomaly/birth defect in the offspring of a study subjects.

  • Number of Subjects With Pregnancies and Their Outcome. [ Time Frame: Up to Month 12. ] [ Designated as safety issue: No ]
    Pregnancy outcome with live infant having no apparent congenital anomaly.

  • Number of Subjects Reporting Clinically Relevant Abnormalities in Biochemical and Haematological Laboratory Parameters Assessed. [ Time Frame: At Day 7, at Months 1, 2, 4, 6 and 7 ] [ Designated as safety issue: No ]
    Laboratory parameters assessed were alanine aminotransferase (ALAT), creatinine (CREA), white blood cells (WBC), neutrophils (NEU), lymphocytes (LYM), monocytes (MON), eosinophils (EOS), basophils (BAS), red blood cells (RBC), haemoglobin (Hgb), haematocrit (Hct) and platelets (PLA). For each parameter and by pre-vaccination status, it was assessed whether the post-vaccination values of the parameter were above, below or in the normal range (missing values are also indicated). Parameters presented in this table are haemoglobin (Hgb) and haematocrit (Hct).

  • Number of Subjects Reporting Clinically Relevant Abnormalities in Biochemical and Haematological Laboratory Parameters Assessed. [ Time Frame: At month 10 and month12. ] [ Designated as safety issue: No ]
    Laboratory parameters assessed were alanine aminotransferase (ALAT), creatinine (CREA), white blood cells (WBC), neutrophils (NEU), lymphocytes (LYM), monocytes (MON), eosinophils (EOS), basophils (BAS), red blood cells (RBC), haemoglobin (Hgb), haematocrit (Hct) and platelets (PLA). For each parameter and by pre-vaccination status, it was assessed whether the post-vaccination values of the parameter were above, below or in the normal range (missing values are also indicated). Parameters presented in this table are ALAT, BAS, CREA, EOS, Hct, Hgb, LYM and MON.

  • Number of Subjects in Each World Health Organisation (WHO) HIV Clinical Stage at Each Time Point by Cluster of Differentiation 4 (CD4+) Cell Count Category at Baseline in All HIV+ Subjects. [ Time Frame: At Months 1, 2, 4, 6 and 7. ] [ Designated as safety issue: No ]

    CD4+ cell count categories, at baseline, assessed were (i) below 200 CD4+ cells per cubic millimetre (mm^3), (ii) between 200 and 500 CD4+ cells/mm^3 and (iii) above 500 CD4+ cells/mm^3.

    WHO classification of HIV-associated clinical disease:

    1. = Asymptomatic HIV-associated symptoms = WHO clinical stage 1
    2. = Mild HIV-associated symptoms = WHO clinical stage 2
    3. = Advanced HIV-associated symptoms = WHO clinical stage 3
    4. = Severe HIV-associated symptoms = WHO clinical stage 4

  • Number of Subjects in Each World Health Organisation (WHO) HIV Clinical Stage at Each Time Point by Cluster of Differentiation 4 (CD4+) Cell Count Category at Baseline in All HIV+ Subjects. [ Time Frame: At Month 10 and Month 12. ] [ Designated as safety issue: No ]
    CD4+ cell count categories, at baseline, assessed were (i) below 200 CD4+ cells per cubic millimetre (mm^3), (ii) between 200 and 500 CD4+ cells/mm^3 and (iii) above 500 CD4+ cells/mm^3. WHO classification of HIV-associated clinical disease: 1 = Asymptomatic HIV-associated symptoms = WHO clinical stage 1 2 = Mild HIV-associated symptoms = WHO clinical stage 2 3 = Advanced HIV-associated symptoms = WHO clinical stage 3 4 = Severe HIV-associated symptoms = WHO clinical stage 4

  • Number of CD4+ Cells Per Cubic Millimeter at Each Time Point in All HIV+ Subjects. [ Time Frame: At pre-vaccination and at Months 1, 2, 4, 6 and 7. ] [ Designated as safety issue: No ]
  • Number of CD4+ Cells Per Cubic Millimetre at Each Time Point in All HIV+ Subjects. [ Time Frame: At Month 10 and Month 12 ] [ Designated as safety issue: No ]
  • HIV Viral Load at Each Time Point in All HIV+ Subjects. [ Time Frame: At pre-vaccination and at Months 1, 2, 4, 6 and 7. ] [ Designated as safety issue: No ]
    The viral load was calculated by estimating the amount of virus in blood samples and was given in number of Ribonucleic acid (RNA) copies per millilitre.

  • HIV Viral Load at Each Time Point in All HIV+ Subjects. [ Time Frame: At Month 10 and Month 12 ] [ Designated as safety issue: No ]
    The viral load was calculated by estimating the amount of virus in blood samples and was given in number of Ribonucleic acid (RNA) copies per millilitre.

  • Number of Seroconverted Subjects for HPV-16 and HPV-18 Antibodies. [ Time Frame: At Months 2 and 7 ] [ Designated as safety issue: No ]

    Seroconversion was defined as the appearance of anti-HPV-16 and/or anti-HPV-18 antibodies (anti-HPV-16 titers ≥ 8 ELISA units per millilitre (EL.U/mL) and anti-HPV-18 titers ≥ 7 EL.U/mL) in the serum of subjects seronegative before vaccination.

    A seronegative subject was a subject whose antibody titres are below the cut-off value.

    Due to the high proportion of initially seropositive subjects in the study population, seroconversion rates were considered for all subjects in the ATP cohort for immunogenicity regardless of baseline serostatus.


  • Number of Seroconverted Subjects for HPV-16 and HPV-18 Antibodies. [ Time Frame: At Month 12 ] [ Designated as safety issue: No ]

    Seroconversion was defined as the appearance of anti-HPV-16 and/or anti-HPV-18 antibodies (anti-HPV-16 titers ≥ 8 ELISA units per millilitre (EL.U/mL) and anti-HPV-18 titers ≥ 7 EL.U/mL) in the serum of subjects seronegative before vaccination.

    A seronegative subject was a subject whose antibody titres are below the cut-off value.

    Due to the high proportion of initially seropositive subjects in the study population, seroconversion rates were considered for all subjects in the ATP cohort for immunogenicity regardless of baseline serostatus.


  • Concentrations for HPV-16 and HPV-18 Antibodies. [ Time Frame: At Months 0, 2 and 7. ] [ Designated as safety issue: No ]

    Concentrations were expressed as geometric mean antibody concentrations (GMCs) and were given in EL.U/mL.

    The antibody concentrations against HPV-16 and HPV-18 were determined by Enzyme-linked immunosorbent assay (ELISA). The cut-off of the assay were 8 EL.U/mL for anti-HPV-16 and 7 EL.U/mL for anti-HPV-18.


  • Concentrations for HPV-16 and HPV-18 Antibodies. [ Time Frame: At Month 12. ] [ Designated as safety issue: No ]

    Concentrations were expressed as geometric mean antibody concentrations (GMCs) and were given in EL.U/mL.

    The antibody concentrations against HPV-16 and HPV-18 were determined by Enzyme-linked immunosorbent assay (ELISA). The cut-off of the assay were 8 EL.U/mL for anti-HPV-16 and 7 EL.U/mL for anti-HPV-18


  • Cell Mediated Immune Response (CMI) (B-cell and T-cell Responses) Related to HPV-16 and HPV-18 Measured by Intracellullar Cytokine Staining (ICS). [ Time Frame: At Months 0, 2, 7 and 12. ] [ Designated as safety issue: No ]
    The CMI response is the measure of the cytokines production (i.e. Cluster of Differentiation 40 Ligand (CD40L), Interferon gamma (IFN-γ), interleukin-2 (IL-2) and tumor necrosis factor alpha (TNF-α)) by HPV-antigen specific T lymphocytes and measured by intracellular cytokine staining assay. The results were expressed as a frequency of positive CD4 or CD8 T cell producing at least 1 cytokine within the CD4 or CD8 T cell sub-population. All doubles= T cell expressing at least 2 cytokines. The CMI analyses for B-cell response were not performed due to a technical issue.

  • Number of Subjects Reporting Clinically Relevant Abnormalities in Biochemical and Haematological Laboratory Parameters Assessed. [ Time Frame: At Day 7, at Months 1, 2, 4, 6 and 7 ] [ Designated as safety issue: No ]

    Laboratory parameters assessed were alanine aminotransferase (ALAT), creatinine (CREA), white blood cells (WBC), neutrophils (NEU), lymphocytes (LYM), monocytes (MON), eosinophils (EOS), basophils (BAS), red blood cells (RBC), haemoglobin (Hgb), haematocrit (Hct) and platelets (PLA).

    For each parameter and by pre-vaccination status, it was assessed whether the post-vaccination values of the parameter were above, below or in the normal range (missing values are also indicated).

    Parameters presented in this table are red blood cells (RBC) and platelets (PLA).


  • Number of Subjects Reporting Clinically Relevant Abnormalities in Biochemical and Haematological Laboratory Parameters Assessed. [ Time Frame: At Day 7, at Months 1, 2, 4, 6 and 7 ] [ Designated as safety issue: No ]

    Laboratory parameters assessed were alanine aminotransferase (ALAT), creatinine (CREA), white blood cells (WBC), neutrophils (NEU), lymphocytes (LYM), monocytes (MON), eosinophils (EOS), basophils (BAS), red blood cells (RBC), haemoglobin (Hgb), haematocrit (Hct) and platelets (PLA).

    For each parameter and by pre-vaccination status, it was assessed whether the post-vaccination values of the parameter were above, below or in the normal range (missing values are also indicated).

    Parameters presented in this table are white blood cells (WBC) and neutrophils (NEU).


  • Number of Subjects Reporting Clinically Relevant Abnormalities in Biochemical and Haematological Laboratory Parameters Assessed. [ Time Frame: At Day 7, at Months 1, 2, 4, 6 and 7 ] [ Designated as safety issue: No ]

    Laboratory parameters assessed were alanine aminotransferase (ALAT), creatinine (CREA), white blood cells (WBC), neutrophils (NEU), lymphocytes (LYM), monocytes (MON), eosinophils (EOS), basophils (BAS), red blood cells (RBC), haemoglobin (Hgb), haematocrit (Hct) and platelets (PLA).

    For each parameter and by pre-vaccination status, it was assessed whether the post-vaccination values of the parameter were above, below or in the normal range (missing values are also indicated).

    Parameters presented in this table are lymphocytes (LYM) and monocytes (MON).


  • Number of Subjects Reporting Clinically Relevant Abnormalities in Biochemical and Haematological Laboratory Parameters Assessed. [ Time Frame: At Day 7, at Months 1, 2, 4, 6 and 7 ] [ Designated as safety issue: No ]

    Laboratory parameters assessed were alanine aminotransferase (ALAT), creatinine (CREA), white blood cells (WBC), neutrophils (NEU), lymphocytes (LYM), monocytes (MON), eosinophils (EOS), basophils (BAS), red blood cells (RBC), haemoglobin (Hgb), haematocrit (Hct) and platelets (PLA).

    For each parameter and by pre-vaccination status, it was assessed whether the post-vaccination values of the parameter were above, below or in the normal range (missing values are also indicated).

    Parameters presented in this table are eosinophils (EOS), basophils (BAS) and creatinine (CREA).


  • Number of Subjects Reporting Clinically Relevant Abnormalities in Biochemical and Haematological Laboratory Parameters Assessed. [ Time Frame: At Day 7, at Months 1, 2, 4, 6 and 7 ] [ Designated as safety issue: No ]

    Laboratory parameters assessed were alanine aminotransferase (ALAT), creatinine (CREA), white blood cells (WBC), neutrophils (NEU), lymphocytes (LYM), monocytes (MON), eosinophils (EOS), basophils (BAS), red blood cells (RBC), haemoglobin (Hgb), haematocrit (Hct) and platelets (PLA).

    For each parameter and by pre-vaccination status, it was assessed whether the post-vaccination values of the parameter were above, below or in the normal range (missing values are also indicated).

    The parameter presented in this table is alanine aminotransferase (ALAT).


  • Number of Subjects Reporting Clinically Relevant Abnormalities in Biochemical and Haematological Laboratory Parameters Assessed. [ Time Frame: At Month 10 and Month 12 ] [ Designated as safety issue: No ]
    Laboratory parameters assessed were alanine aminotransferase (ALAT), creatinine (CREA), white blood cells (WBC), neutrophils (NEU), lymphocytes (LYM), monocytes (MON), eosinophils (EOS), basophils (BAS), red blood cells (RBC), haemoglobin (Hgb), haematocrit (Hct) and platelets (PLA). For each parameter and by pre-vaccination status, it was assessed whether the post-vaccination values of the parameter were above, below or in the normal range (missing values are also indicated). Parameters presented in this table are NEU, PLA, RBC and WBC.


Enrollment: 150
Study Start Date: January 2008
Study Completion Date: July 2011
Primary Completion Date: February 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: HIV+/Cervarix Group
Human immunodeficiency virus positive (HIV+) subjects received 3 doses of Cervarix™ vaccine at Day 0, Month 1 and Month 6. Cervarix™ vaccines was administrated by intramuscular injection into the deltoid region of the non-dominant arm according to a 0, 1, 6 month schedule.
Biological: Cervarix TM
Intramuscular injection, 3 doses
Active Comparator: HIV+/Aluminium Hydroxide Group
Human immunodeficiency virus positive (HIV+) subjects received 3 doses of control Aluminium Hydroxide [Al(OH)3] vaccine at Day 0, Month 1 and Month 6. Aluminium Hydroxide vaccine was administrated by intramuscular injection into the deltoid region of the non-dominant arm according to a 0, 1, 6 month schedule.
Biological: Placebo Control
Intramuscular injection, 3 doses
Experimental: HIV-/Cervarix Group
Human immunodeficiency virus negative (HIV-) subjects received 3 doses of Cervarix™ vaccine at Day 0, Month 1 and Month 6. Cervarix™ vaccines was administrated by intramuscular injection into the deltoid region of the non-dominant arm according to a 0, 1, 6 month schedule.
Biological: Cervarix TM
Intramuscular injection, 3 doses

  Eligibility

Ages Eligible for Study:   18 Years to 25 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Subjects who the investigator believes that they can and will comply with the requirements of the protocol
  • A female between, and including, 18 and 25 years of age at the time of the first vaccination.
  • Written, signed or thumb-printed informed consent obtained from the subject prior to enrolment.
  • Subjects willing to undergo HIV Voluntary Counseling and Testing (VCT) and willing to be informed of their HIV status.
  • Subjects willing to provide place of residence and be visited at home.
  • HIV seropositive subjects:

    1. Subjects must be HIV seropositive according to WHO case definition
    2. Subjects with WHO Clinical Stage 1 HIV-associated disease
    3. Subjects currently on antiretroviral therapy (ART) must be compliant to ART and have undetectable viral load
  • HIV seronegative subjects: Subjects confirmed as HIV seronegative at the screening visit are eligible to participate in the HIV-/HPV group of the study.
  • Non-virgin subjects must have a normal colposcopy at the screening visit.
  • Non-virgin subjects must have a normal cervical cytology (Pap smear) or no greater than atypical squamous cells of undetermined significance (ASC-US) at the screening visit.
  • All subjects must have a negative urine pregnancy test at the screening visit and at visit 1 (Day 0).
  • Subjects must be of non-childbearing potential or, if of childbearing potential, must be abstinent or have used adequate contraceptive precautions for 30 days prior to vaccination, have a negative pregnancy test and must agree to continue such precautions for two months after completion of the vaccination series.
  • Subjects must have had no more than 6 life-time sexual partners prior to enrolment.
  • Subjects must have one single intact cervix

Exclusion Criteria:

  • Active tuberculosis (TB)
  • Current TB prophylaxis or therapy.
  • Anemia at the screening visit.
  • increased creatinine at the screening visit.
  • Increased hepatic enzym (ALT) at the screening visit
  • Use of any investigational or non-registered product (drug or vaccine) other than the study vaccine within 30 days preceding the first dose of study vaccine/control, or planned use during the entire study period (up to Month 12).
  • Chronic administration of immunosuppressants or other immune-modifying drugs within 6 months prior to the first vaccine dose.
  • Administration of a vaccine not foreseen by the study protocol within 30 days before the first dose of study vaccine/control. Enrolment will be postponed until the subject is outside the specified window.
  • Planned administration of a vaccine not foreseen by the study protocol within 30 days before or 30 days after (i.e., Days 0-29) any dose of study vaccine.
  • Previous vaccination against HPV, or planned administration of any HPV vaccine other than that foreseen by the study protocol during the study period (Month 0 to Month 12).
  • previous administration of components of the investigational vaccine
  • Cancer or autoimmune disease under treatment.
  • Hypersensitivity to latex.
  • History of allergic disease or reactions likely to be exacerbated by any component of the vaccine/control.
  • Acute disease at the time of enrolment.
  • Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic or renal functional abnormality, as determined by physical examination or laboratory testing performed at the screening visit.
  • History of any neurological disorders or seizures.
  • Pregnant or breastfeeding female.
  • A subject planning to become pregnant, likely to become pregnant (as determined by the investigator) or planning to discontinue contraceptive precautions during the study period, up to two months after the last vaccine dose.
  • Concurrently participating in another clinical study, at any time during the study period (up to Month 12), in which the subject has been or will be exposed to an investigational or a non-investigational product (pharmaceutical product or device).
  • Any medically diagnosed or suspected immunodeficient condition (other than HIV for HIV seropositive subjects), based on medical history, physical examination and/or laboratory tests results.
  • Administration of immunoglobulins and/or any blood products within the three months preceding the first dose of study vaccine/control or planned administration during the study period. Enrolment will be postponed until the subject is outside the specified window.
  • Administration of trimethoprim/sulphamethoxazole within 7 days before the first dose of study vaccine/control, or planned administration of trimethoprim/sulphamethoxazole within 7 days after the first dose of study vaccine/control.
  • Current drugs or alcohol abuse.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00586339

Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided by GlaxoSmithKline

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT00586339     History of Changes
Other Study ID Numbers: 107863
Study First Received: December 21, 2007
Results First Received: February 16, 2012
Last Updated: July 19, 2012
Health Authority: South Africa: Medicines Control Council

Keywords provided by GlaxoSmithKline:
HPV
Human papillomavirus (HPV) vaccine
Human Immunodeficiency Virus (HIV)
Cervical cancer
Papillomavirus

Additional relevant MeSH terms:
Acquired Immunodeficiency Syndrome
HIV Infections
Neoplasms
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Slow Virus Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Aluminum Hydroxide
Adjuvants, Immunologic
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antacids
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on April 15, 2014