- ICH GCP
- US-Register für klinische Studien
- Klinische Studie NCT00819390
Chloroquine for Reducing Immune Activation in HIV- Infected Individuals
A Phase II, Double Blind, Randomized, Exploratory Study of Chloroquine for Reducing HIV-Associated Immune Activation
HIV is characterized by frequent immune system activation. Early in the course of infection the body establishes an immune activation "set point" related to the amount of HIV in the blood stream. This set point affects the rate of CD4 cell loss. Without CD4 cells, or with very low levels of CD4 cells, the body cannot fight off illness. This is known as immunodeficiency. If left untreated HIV can lead to extreme immunodeficiency and AIDS.
Evidence suggests that by decreasing the rate of immune system activation, immune deficiency progression could be prevented. The purpose of this study is to learn how well chloroquine can reduce the level of immune activation and to test the safety and tolerance of chloroquine in people infected with HIV.
Studienübersicht
Status
Bedingungen
Intervention / Behandlung
Detaillierte Beschreibung
HIV is characterized by persistent immune system activation, and early in the course of infection the body establishes an immune activation "set point" related to the amount of HIV in the blood stream. This set point affects the rate of CD4 cell loss. Without CD4 cells, or with very low levels of CD4 cells, the body cannot fight off illness. This is known as immunodeficiency. If left untreated HIV can lead to extreme immunodeficiency and AIDS.
Immune system activation includes activating the CD8 cells. These cells attack body cells infected with viruses. Because of this, CD4 cells infected with HIV are frequently destroyed by CD8 cells. The purpose of this study is to learn how well chloroquine reduces the level of activation of CD8 cells in people infected with HIV. Increased activation of CD8 cells is thought to lead to a more severe path of disease in HIV infection.
The constant immune activation observed in HIV- infected patients has also been linked to higher levels of byproducts from certain naturally occurring bacteria found in the gut that are known to be immune stimulants. By decreasing the stimulation from these byproducts with chloroquine treatment, HIV disease may be slowed.
The purpose of this study was to learn how well chloroquine reduces the level of activation of CD8 cells and lowers the levels of bacteria byproducts in people infected with HIV, either off antiretroviral therapy (ART) (protocol version 1.0 dated December 17, 2008) or on-ART (protocol version 2.0 dated October 1, 2010). The off-ART (Arms A and B) and on-ART (Arms C and D) participants were enrolled during different time periods, and the study was designed to analyze the two study populations separately. This study also looked at how well chloroquine was tolerated and its safety in HIV- infected participants.
Off-ART participants in the study were randomized with equal probability to one of two treatment arms:
Arm A: Participants received 12 weeks of chloroquine treatment followed by 12 weeks of placebo
Arm B: Participants received 12 weeks of placebo followed by 12 weeks of chloroquine
On-ART participants in the study were randomized with equal probability to one of two treatment arms:
Arm C: Participants received 12 weeks of chloroquine treatment followed by 12 weeks of placebo
Arm D: Participants received 12 weeks of placebo followed by 12 weeks of chloroquine
Study treatment was given once a day for a full 24 weeks. There was an additional 4 weeks of follow-up for purposes of safety. After treatment has started, participants were asked to come to the clinic on Weeks 4, 10, 12, 16, 22, and 24. At each visit participants were given enough study treatment to last until the next visit. Each visit lasted between 30 and 60 minutes. At most visits, participants had a physical exam, answered questions about any medications they were taking and how they are feeling, and had blood drawn for safety to assess CD4/CD8 cell counts and viral load. Some additional blood were also stored for immunology testing. At some visits, participants were asked questions about their medication and medical history, had pupils dilated, had a hearing test, and had an electrocardiogram (EKG). Some visits required participants to arrive fasting. Pregnancy tests were also conducted if the participant is able to become pregnant or if pregnancy was suspected.
Studientyp
Einschreibung (Tatsächlich)
Phase
- Phase 2
Kontakte und Standorte
Studienorte
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Alabama
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Birmingham, Alabama, Vereinigte Staaten, 35294
- Alabama Therapeutics CRS (5801)
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California
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San Diego, California, Vereinigte Staaten, 92103
- Ucsd, Avrc Crs (701)
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Colorado
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Aurora, Colorado, Vereinigte Staaten, 80045
- University of Colorado Hospital CRS (6101)
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District of Columbia
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Washington, District of Columbia, Vereinigte Staaten, 20007
- Georgetown University CRS (GU CRS) (1008)
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Maryland
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Baltimore, Maryland, Vereinigte Staaten, 21205
- Johns Hopkins Adult AIDS CRS (201)
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Massachusetts
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Boston, Massachusetts, Vereinigte Staaten, 02114
- Massachusetts General Hospital ACTG CRS (101)
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Missouri
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St. Louis, Missouri, Vereinigte Staaten, 63110
- Washington University CRS (2101)
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New York
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New York, New York, Vereinigte Staaten, 10011
- Cornell CRS (7804)
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North Carolina
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Chapel Hill, North Carolina, Vereinigte Staaten, 27514
- Unc Aids Crs (3201)
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Ohio
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Cincinnati, Ohio, Vereinigte Staaten, 45267
- Univ. of Cincinnati CRS (2401)
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Cleveland, Ohio, Vereinigte Staaten, 44106
- Case CRS (2501)
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Cleveland, Ohio, Vereinigte Staaten, 44109
- MetroHealth CRS (2503)
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Pennsylvania
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Philadelphia, Pennsylvania, Vereinigte Staaten, 19104
- Hosp. of the Univ. of Pennsylvania CRS (6201)
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Pittsburgh, Pennsylvania, Vereinigte Staaten, 15213
- Pittsburgh CRS (1001)
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Tennessee
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Nashville, Tennessee, Vereinigte Staaten, 37204
- Vanderbilt Therapeutics CRS (3652)
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Teilnahmekriterien
Zulassungskriterien
Studienberechtigtes Alter
Akzeptiert gesunde Freiwillige
Studienberechtigte Geschlechter
Beschreibung
Inclusion Criteria:
- HIV-1 infected
- Certain specified laboratory values obtained within 30 days prior to study entry. More information on this criterion can be found in the study protocol.
- Documentation that pre-entry specimen for the primary immune activation endpoint responses has been obtained
- Female participants of reproductive potential must have a negative pregnancy test performed within 24 hours prior to study entry
- If engaging in sexual activity, female participants must use adequate forms of contraception while receiving study treatment and for 4 weeks after stopping the treatment. More information on this criterion can be found in the study protocol.
- Ability and willingness to provide informed consent
Additional Inclusion Criteria for Off-ART Participants:
- No antiretroviral therapy (ART) for at least 6 months prior to study entry and not likely to start within the 6 months after study entry
- CD4 cell count greater than or equal to 400 cells/mm3 at screening, obtained within 30 days prior to study entry
- For participants with previous ART use, documentation or recall of nadir CD4 cell count greater than or equal to 200 cells/mm3
- HIV-1 RNA viral load greater than or equal to 1,000 copies/mL obtained within 30 days prior to study entry
- No history of CDC category C AIDS-related opportunistic infections
- Karnofsky performance score greater than or equal to 70 within 30 days prior to study entry
Additional Inclusion Criteria for On-ART Participants:
- Receiving ART, defined as a regimen that includes three or more antiretroviral medications, for at least 24 months prior to study entry
- Required documentation that all HIV-1 viral loads (at least two) were below 400 copies/mL. More information on this criterion can be found in the study protocol.
- Screening HIV-1 RNA <200 copies/mL within 30 days prior to study entry. More information on this criterion can be found in the study protocol.
- CD4 cell count <350 cells/mm3 at screening, obtained within 30 days prior to study entry
Exclusion Criteria:
- Continuous use of certain specified medication for more than 3 days within 30 days prior to study entry. More information on this criterion can be found in the study protocol.
- Use of chloroquine or hydroxychloroquine within 3 months prior to study entry
- Known history of hypersensitivity to 4-aminoquinoline compounds (such as chloroquine or hydroxychloroquine)
- Active drug or alcohol use or dependence that, in the opinion of the investigator would interfere with adherence to study requirements
- Serious illness requiring systemic treatment and/or hospitalization within 30 days prior to study entry
- Renal insufficiency, defined as serum creatinine greater than 1.5 mg/dL, within 30 days prior to study entry
- History of retinal disease (i.e. confirmed retinopathy by ophthalmologic examination)
- History of neoplasm, within 5 years prior to study entry, other than treated in situ carcinoma or basal-cell or localized squamous cell carcinoma of the skin
- Glucose-6-phosphate dehydrogenase (G6PD) deficiency at screening
- History of porphyria
- History of psoriasis
- History of cirrhosis
- History of seizure disorder
- History of tinnitus (ear and/or head noise lasting more than 5 minutes that occurs more often than once per week) or history of sudden hearing loss
- History of myopathy
- History of cardiac conduction abnormality or cardiomyopathy. More information on this criterion can be found in the study protocol.
Additional Exclusion Criteria for On-ART Participants:
- Plans to change ART regimen with the 6 months after study entry (change in ART regimen is only permitted if due to toxicity)
Studienplan
Wie ist die Studie aufgebaut?
Designdetails
- Hauptzweck: Behandlung
- Zuteilung: Zufällig
- Interventionsmodell: Crossover-Aufgabe
- Maskierung: Vervierfachen
Waffen und Interventionen
Teilnehmergruppe / Arm |
Intervention / Behandlung |
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Experimental: A: Chloroquine then Placebo for Off-ART Participants
Participants received chloroquine treatment from Day 0 through the Week 12 study visit and then began chloroquine placebo treatment until the Week 24 study visit.
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Taken orally, once daily, at a dose of 250 mg for 12 weeks.
Taken orally, once daily for 12 weeks.
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Experimental: B: Placebo then Chloroquine for Off-ART Participants
Participants received chloroquine placebo treatment from Day 0 through the Week 12 study visit and then began chloroquine treatment until the Week 24 study visit.
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Taken orally, once daily, at a dose of 250 mg for 12 weeks.
Taken orally, once daily for 12 weeks.
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Experimental: C: Chloroquine then Placebo for On-ART Participants
Participants received chloroquine treatment from Day 0 through the Week 12 study visit and then began chloroquine placebo treatment until the Week 24 study visit.
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Taken orally, once daily, at a dose of 250 mg for 12 weeks.
Taken orally, once daily for 12 weeks.
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Experimental: D: Placebo then Chloroquine for On-ART Participants
Participants received chloroquine placebo treatment from Day 0 through the Week 12 study visit and then began chloroquine treatment until the Week 24 study visit.
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Taken orally, once daily, at a dose of 250 mg for 12 weeks.
Taken orally, once daily for 12 weeks.
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Was misst die Studie?
Primäre Ergebnismessungen
Ergebnis Maßnahme |
Maßnahmenbeschreibung |
Zeitfenster |
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Change in Percent CD8 HLA-DR+/CD38+ From Baseline to Week 12
Zeitfenster: At pre-entry, entry, weeks 10 and 12
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The baseline percent CD8 HLA-DR+/CD38+ (mean of pre-entry and entry percent CD8 HLA-DR+/CD38+) was subtracted from the mean of week 10 and week 12 percent CD8 HLA-DR+/CD38+.
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At pre-entry, entry, weeks 10 and 12
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Sekundäre Ergebnismessungen
Ergebnis Maßnahme |
Maßnahmenbeschreibung |
Zeitfenster |
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Change in Percent CD8 HLA-DR+/CD38+ From Start to End of the 12-week Chloroquine Treatment Period
Zeitfenster: For Arms A and C: Pre-entry, entry, weeks 10 and 12. For Arms B and D: Weeks 10, 12, 22 and 24
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For Arm A: Chloroquine then Placebo for off-ART participants and Arm C: Chloroquine then Placebo for on-ART participants, the baseline percent CD8 HLA-DR+/CD38+ (mean of pre-entry and entry percent CD8 HLA-DR+/CD38+) was subtracted from the mean of week 10 and week 12 percent CD8 HLA-DR+/CD38+.
For Arm B: Placebo then Chloroquine for off-ART participants and Arm D: Placebo then Chloroquine for on-ART participants, the mean of week 10 and week 12 percent CD8 HLA-DR+/CD38+ was subtracted from the mean of week 22 and week 24 percent CD8 HLA-DR+/CD38+.
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For Arms A and C: Pre-entry, entry, weeks 10 and 12. For Arms B and D: Weeks 10, 12, 22 and 24
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Change in Percent CD8 HLA-DR+/CD38+ From Week 12 to Week 24
Zeitfenster: At Weeks 10, 12, 22 and 24
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The mean of week 10 and week 12 percent CD8 HLA-DR+/CD38+ is subtracted from the mean of the week 22 and week 24 percent CD8 HLA-DR+/CD38+
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At Weeks 10, 12, 22 and 24
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Change in Percent CD8 HLA-DR+/CD38+ From Baseline to Week 24 in Arm A and Arm C
Zeitfenster: At Pre-entry, entry, Weeks 22 and 24
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The baseline percent CD8 HLA-DR+/CD38+ (mean of pre-entry and entry percent CD8 HLA-DR+/CD38+) was subtracted from the mean of week 22 and week 24 percent CD8 HLA-DR+/CD38+.
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At Pre-entry, entry, Weeks 22 and 24
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Change in Total CD4 T Cell Count From Baseline to Week 12
Zeitfenster: At pre-entry, entry, weeks 10 and 12
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Baseline CD4 count (mean of pre-entry and entry CD4 count) is subtracted from the mean of week 10 and week 12 CD4 count
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At pre-entry, entry, weeks 10 and 12
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Number of Participants With Events Grade 3 or Higher
Zeitfenster: From start of study treatment to study completion at week 28
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Events included signs and symptoms, laboratory abnormalities and/or clinical events grade 3 or higher which were described by site clinician blinded to the treatment arm as definitely or possibly related to the study treatment.
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From start of study treatment to study completion at week 28
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HIV-1 RNA Copies/mL at Study Entry for Off-ART Participants
Zeitfenster: At Entry
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Results reported are for HIV-1 RNA (copies/mL) at study entry for off-ART participants.
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At Entry
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HIV-1 RNA Copies/mL at Weeks 12 and 24 for Off-ART Participants
Zeitfenster: At weeks 12 and 24
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Results reported are for HIV-1 RNA (copies/mL) at week 12 and week 24 for off-ART participants.
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At weeks 12 and 24
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HIV-1 RNA Copies/mL at Study Entry for On-ART Participants
Zeitfenster: At Entry
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Results reported are for HIV-1 RNA at study entry for on-ART participants.
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At Entry
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HIV-1 RNA Copies/mL at Week 12 for On-ART Participants
Zeitfenster: At week 12
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Results reported are for HIV-1 RNA at week 12 for on-ART participants.
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At week 12
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HIV-1 RNA Copies/mL at Week 24 for On-ART Participants
Zeitfenster: At week 24
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Results reported are for HIV-1 RNA at week 24 for on-ART participants.
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At week 24
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Percent CD8 CD38+ at Baseline
Zeitfenster: At pre-entry and entry
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Baseline CD8 CD38+ is computed as the mean of pre-entry and entry CD8 CD38+.
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At pre-entry and entry
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Percent CD8 CD38+ at Week 12
Zeitfenster: At Week 12
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Results reported are the week 12 percentage of CD8 expressing CD38+.
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At Week 12
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Percent CD8 CD38+ at Week 24
Zeitfenster: At Week 24
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Results reported are the week 24 percentage of CD8 expressing CD38+.
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At Week 24
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Percent CD4 HLA-DR+/CD38+ at Baseline
Zeitfenster: At pre-entry and entry
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Baseline CD4 HLA-DR+/CD38+ is computed as the mean of pre-entry and entry CD4 HLA-DR+/CD38+.
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At pre-entry and entry
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Percent CD4 HLA-DR+/CD38+ at Week 12
Zeitfenster: At Week 12
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Results reported are the week 12 percentage of CD4 expressing HLA-DR+/CD38+.
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At Week 12
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Percent CD4 HLA-DR+/CD38+ at Week 24
Zeitfenster: At Week 24
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Results reported are the week 24 percentage of CD4 expressing HLA-DR+/CD38+.
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At Week 24
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IL-6, Soluble TNF-rI (sTNF-rI) and D-dimer at Baseline
Zeitfenster: At pre-entry and entry
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Baseline IL-6, sTNF-rI and D-dimer were computed as the mean of pre-entry and entry IL-6, sTNF-rI and D-dimer, respectively.
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At pre-entry and entry
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IL-6, Soluble TNF-rI (sTNF-rI) and D-dimer at Week 12
Zeitfenster: At week 12
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Results reported are the week 12 IL-6, sTNF-rI and D-dimer.
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At week 12
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IL-6, Soluble TNF-rI (sTNF-rI) and D-dimer at Week 24
Zeitfenster: At week 24
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Results reported are the week 24 IL-6, sTNF-rI and D-dimer.
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At week 24
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Soluble CD14 (sCD14) at Baseline
Zeitfenster: At pre-entry and entry
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Baseline sCD14 was computed as the mean of pre-entry and entry sCD14.
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At pre-entry and entry
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Soluble CD14 (sCD14) at Week 12
Zeitfenster: At week 12
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Results reported are the week 12 sCD14.
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At week 12
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Soluble CD14 (sCD14) at Week 24
Zeitfenster: At week 24
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Results reported are the week 24 sCD14.
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At week 24
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Fasting Lipopolysaccharides (LPS) at Entry
Zeitfenster: At entry
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Results reported are for entry fasting LPS.
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At entry
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Fasting Lipopolysaccharides (LPS) at Week 12
Zeitfenster: At week 12
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Results reported are the week 12 fasting LPS.
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At week 12
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Fasting Lipopolysaccharides (LPS) at Week 24
Zeitfenster: At week 24
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Results reported are the week 24 fasting LPS.
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At week 24
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Percent Activation Levels of Plasmacytoid Dendritic Cells (pDC) and Myeloid Dendritic Cells (mDC) at Baseline
Zeitfenster: At pre-entry and entry
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Baseline percent activation levels of pDC were computed as the mean of pre-entry and entry percent activation levels of pDC.
Similarly, baseline percent activation levels of mDC were computed as the mean of pre-entry and entry percent activation levels of mDC.
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At pre-entry and entry
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Percent Activation Levels of Plasmacytoid Dendritic Cells (pDC) and Myeloid Dendritic Cells (mDC) at Week 12
Zeitfenster: At week 12
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Results reported are the week 12 percent activation levels of pDC and mDC.
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At week 12
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Percent Activation Levels of Plasmacytoid Dendritic Cells (pDC) and Myeloid Dendritic Cells (mDC) at Week 24
Zeitfenster: At week 24
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Results reported are the week 24 percent activation levels of pDC and mDC.
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At week 24
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Mitarbeiter und Ermittler
Sponsor
Ermittler
- Studienstuhl: Jeffrey M Jacobson, MD, Drexel University College of Medicine
Publikationen und hilfreiche Links
Allgemeine Veröffentlichungen
- Savarino A, Boelaert JR, Cassone A, Majori G, Cauda R. Effects of chloroquine on viral infections: an old drug against today's diseases? Lancet Infect Dis. 2003 Nov;3(11):722-7. doi: 10.1016/s1473-3099(03)00806-5.
- Neely M, Kalyesubula I, Bagenda D, Myers C, Olness K. Effect of chloroquine on human immunodeficiency virus (HIV) vertical transmission. Afr Health Sci. 2003 Aug;3(2):61-7.
- Semrau K, Kuhn L, Kasonde P, Sinkala M, Kankasa C, Shutes E, Vwalika C, Ghosh M, Aldrovandi G, Thea DM. Impact of chloroquine on viral load in breast milk. Trop Med Int Health. 2006 Jun;11(6):800-3. doi: 10.1111/j.1365-3156.2006.01645.x.
- Jacobson JM, Bosinger SE, Kang M, Belaunzaran-Zamudio P, Matining RM, Wilson CC, Flexner C, Clagett B, Plants J, Read S, Purdue L, Myers L, Boone L, Tebas P, Kumar P, Clifford D, Douek D, Silvestri G, Landay AL, Lederman MM. The Effect of Chloroquine on Immune Activation and Interferon Signatures Associated with HIV-1. AIDS Res Hum Retroviruses. 2016 Jul;32(7):636-47. doi: 10.1089/AID.2015.0336. Epub 2016 Apr 19.
Studienaufzeichnungsdaten
Haupttermine studieren
Studienbeginn
Primärer Abschluss (Tatsächlich)
Studienabschluss (Tatsächlich)
Studienanmeldedaten
Zuerst eingereicht
Zuerst eingereicht, das die QC-Kriterien erfüllt hat
Zuerst gepostet (Schätzen)
Studienaufzeichnungsaktualisierungen
Letztes Update gepostet (Schätzen)
Letztes eingereichtes Update, das die QC-Kriterien erfüllt
Zuletzt verifiziert
Mehr Informationen
Begriffe im Zusammenhang mit dieser Studie
Zusätzliche relevante MeSH-Bedingungen
- RNA-Virusinfektionen
- Viruserkrankungen
- Infektionen
- Durch Blut übertragene Infektionen
- Übertragbare Krankheiten
- Sexuell übertragbare Krankheiten, viral
- Sexuell übertragbare Krankheiten
- Lentivirus-Infektionen
- Retroviridae-Infektionen
- Immunologische Mangelsyndrome
- Erkrankungen des Immunsystems
- HIV-Infektionen
- Antiinfektiva
- Antirheumatika
- Antiprotozoenmittel
- Antiparasitäre Mittel
- Antimalariamittel
- Amebizide
- Chloroquin
Andere Studien-ID-Nummern
- ACTG A5258
- 1U01AI068636 (US NIH Stipendium/Vertrag)
Diese Informationen wurden ohne Änderungen direkt von der Website clinicaltrials.gov abgerufen. Wenn Sie Ihre Studiendaten ändern, entfernen oder aktualisieren möchten, wenden Sie sich bitte an register@clinicaltrials.gov. Sobald eine Änderung auf clinicaltrials.gov implementiert wird, wird diese automatisch auch auf unserer Website aktualisiert .
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