Encochleated Oral Amphotericin for Cryptococcal Meningitis Trial
Encochleated Oral Amphotericin for Cryptococcal Meningitis Trial
批准号:
10163929
负责人:
David R Boulware
金额:
$63.22万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-03-01 至 2023-02-28
关键词:
Acquired Immunodeficiency SyndromeAdultAfricaAfrica South of the SaharaAfricanAmphotericinAmphotericin BAntifungal AgentsAntifungal TherapyAspergillusBlastomycosisBotswanaCandida aurisCare given by nursesCaringCentral Nervous System InfectionsCessation of lifeChronic Mucocutaneous CandidiasisCold ChainsCombined Modality TherapyConsolidation TherapyControl GroupsCountryCryptococcal MeningitisCryptococcusDataDiagnosisDoseDrug KineticsElectricityFailureFluconazoleFlucytosineFormulationFungal MeningitisFutureGoalsGoldHIVHIV antiretroviralHistoplasmosisHospitalizationHospitalsHumanIgEImmunocompromised HostIncidenceIndustrial fungicideInfectionInternationalIntravenousJob&aposs SyndromeLaboratoriesLipoproteinsLiposomesMedicineMeningitisMetabolic Clearance RateMicrobiologyModelingMonitorMorbidity - disease rateMycosesNIH MouseNational Institute of Allergy and Infectious DiseaseNeoadjuvant TherapyNeurologicNeurological outcomeOpportunistic InfectionsOralOutpatientsPersonsPhasePhase I/II TrialPhase III Clinical TrialsProphylactic treatmentRandomizedResistant candidaResourcesSafetySample SizeShippingSouth AfricaSterilizationSurrogate EndpointSurvivorsTestingTimeToxic effectTransplant RecipientsUgandaUnited StatesUnited States National Institutes of HealthWorkYeastsantiretroviral therapyattributable mortalitybaseclinical applicationclinical carecostdata modelingdeoxycholatedisabilityextracellularfungusimprovedinnovationmacrophagemonocytemortalitymouse modelnephrotoxicitynovelphase 2 studyphase I trialphase II trialroutine careside effectsoystandard of carevirology
中文摘要
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英文摘要
Fungal infections are a common cause of opportunistic infections in immunocompromised persons. Among
the most severe infections is fungal meningitis. Cryptococcal meningitis is the most common cause of adult
meningitis in Africa, and Cryptococcus causes 15% of AIDS-related mortality globally.
Amphotericin B combination antifungal is the recommended therapy for cryptococcal meningitis; however,
in Sub-Saharan Africa outside of South Africa, amphotericin is rarely available in routine care. Barriers to
amphotericin availability and use include cold chain shipping and storage at 4⁰C, IV administration, and toxicity.
In the United States, the necessity on IV amphotericin administration prolongs hospitalization, increasing costs.
However, an innovative orally-absorbed encochleated amphotericin B (cAMB) has been developed. In
brief, this is amphotericin B wrapped in a soy-based lipoprotein (i.e. cochleate) that is absorbed and taken up
by monocytes and macrophages for targeted intra-cellular delivery. As such cAMB achieves high intracellular
concentrations where the phagocytosed yeast reside but low extracellular concentrations, resulting in minimal
systemic and nephrotoxicity. In intramural NIH mouse studies, oral cAMB at 25 mg/kg/day with flucytosine has
similar survival as injected amphotericin and flucytosine, which is considered the goal standard of therapy.
Human phase I single ascending dose studies have been completed in the U.S. where 200-800mg doses
have been well tolerated with only mild GI side effects observed at 800mg given as a single dose. An ongoing
NIH phase II trial of chronic mucocutaneous candidiasis (n=3) in persons living with hyper-IgE Job syndrome
has demonstrated safety and efficacy of 400mg cAMB taken 1-2x daily (i.e. up to 800mg/day) for >12 months.
We propose to conduct phase I multiple ascending dose finding trial to determine pharmacokinetics, safety,
and oral tolerability of cAMB administered in multiple doses per day in Africans. Second, we will conduct a
phase II trial to investigate the 8-week safety and tolerability as consolidation therapy. Third, we will investigate
microbiologic effects of cAMB on CSF Cryptococcus clearance rate in Ugandans with cryptococcal meningitis.
Specific Aims:
1. Determine the pharmacokinetic, safety, and tolerability of encochleated oral cAMB given in multiple doses
per day to discover the maximum safe and tolerable daily dose.
2. Determine the longer-term safety and efficacy of oral cAMB when used for cryptococcal meningitis
consolidation antifungal therapy from 2 to 10 weeks after meningitis diagnosis.
3. Determine if an encochleated oral cAMB achieves non-inferior rate of CSF Cryptococcus clearance as
compared to IV amphotericin B in HIV-infected Ugandans with cryptococcal meningitis.
Hypotheses: We hypothesize that cAMB is well tolerated at ~25mg/kg/day in divided doses, orally absorbed
and will have a non-inferior rate of CSF sterilization compared with IV amphotericin in cryptococcal meningitis.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Encochleated Oral Amphotericin for HIV-related Cryptococcal Meningitis Trial: Phase 3 Trial
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批准号:10619788
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项目类别:
-
资助金额:$214.51万
-
财政年份:2023
-
负责人:David R Boulware
-
依托单位:
11th International Conference on Cryptococcus and Cryptococcosis (ICCC)
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批准号:10399173
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项目类别:
-
资助金额:$1.7万
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财政年份:2022
-
负责人:David R Boulware
-
依托单位:
TB Meningitis: Evaluating CSF Immunology to Discover Hidden Disease and Potential Immunomodulatory Therapies
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批准号:10335501
-
项目类别:
-
资助金额:$69.62万
-
财政年份:2021
-
负责人:David R Boulware
-
依托单位:
TB Meningitis: Evaluating CSF Immunology to Discover Hidden Disease and Potential Immunomodulatory Therapies
-
批准号:10459614
-
项目类别:
-
资助金额:$67.08万
-
财政年份:2021
-
负责人:David R Boulware
-
依托单位:
TB Meningitis: Evaluating CSF Immunology to Discover Hidden Disease and Potential Immunomodulatory Therapies
-
批准号:10675513
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项目类别:
-
资助金额:$66.07万
-
财政年份:2021
-
负责人:David R Boulware
-
依托单位:
Encochleated Oral Amphotericin for Cryptococcal Meningitis Trial
-
批准号:10364704
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项目类别:
-
资助金额:$62.6万
-
财政年份:2019
-
负责人:David R Boulware
-
依托单位:
Cryptococcal Antigen Screening plus Sertraline (C-ASSERT)
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批准号:9271847
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项目类别:
-
资助金额:$64.69万
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财政年份:2016
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负责人:David R Boulware
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依托单位:
Phased Implementation of a Public Health Programme: Cryptococcal Screening and Treatment in South Africa
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批准号:9232071
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项目类别:
-
资助金额:$57.82万
-
财政年份:2016
-
负责人:David R Boulware
-
依托单位:
Cryptococcal Antigen Screening plus Sertraline (C-ASSERT)
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批准号:9925177
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项目类别:
-
资助金额:$67.04万
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财政年份:2016
-
负责人:David R Boulware
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依托单位:
Cryptococcal Antigen Screening plus Sertraline (C-ASSERT)
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批准号:9914429
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项目类别:
-
资助金额:$11.66万
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财政年份:2016
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负责人:David R Boulware
-
依托单位:
Improving Diagnostics and Neurocognitive Outcomes in HIV/AIDS-related Meningitis
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批准号:10395979
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项目类别:
-
资助金额:$62.63万
-
财政年份:2013
-
负责人:David R Boulware
-
依托单位:
Improving Diagnostics and Neurocognitive Outcomes in HIV/AIDS-related Meningitis
-
批准号:8651643
-
项目类别:
-
资助金额:$64.92万
-
财政年份:2013
-
负责人:David R Boulware
-
依托单位:
Improving Diagnostics and Neurocognitive Outcomes in HIV/AIDS-related Meningitis
-
批准号:9981024
-
项目类别:
-
资助金额:$63.82万
-
财政年份:2013
-
负责人:David R Boulware
-
依托单位:
Improving Diagnostics and Neurocognitive Outcomes in HIV/AIDS-related Meningitis
-
批准号:9301658
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项目类别:
-
资助金额:$63.66万
-
财政年份:2013
-
负责人:David R Boulware
-
依托单位:
Improving Diagnostics and Neurocognitive Outcomes in HIV/AIDS-related Meningitis
-
批准号:10619543
-
项目类别:
-
资助金额:$62.07万
-
财政年份:2013
-
负责人:David R Boulware
-
依托单位:
Improving Diagnostics and Neurocognitive Outcomes in HIV/AIDS-related Meningitis
-
批准号:8723322
-
项目类别:
-
资助金额:$63.03万
-
财政年份:2013
-
负责人:David R Boulware
-
依托单位:
Trial for the Optimal Timing of HIV Therapy after Cryptococcal Meningitis
-
批准号:8507138
-
项目类别:
-
资助金额:$139.53万
-
财政年份:2010
-
负责人:David R Boulware
-
依托单位:
Trial for the Optimal Timing of HIV Therapy after Cryptococcal Meningitis
-
批准号:8291369
-
项目类别:
-
资助金额:$148.43万
-
财政年份:2010
-
负责人:David R Boulware
-
依托单位:
Trial for the Optimal Timing of HIV Therapy after Cryptococcal Meningitis
-
批准号:7930088
-
项目类别:
-
资助金额:$169.2万
-
财政年份:2010
-
负责人:David R Boulware
-
依托单位:
Trial for the Optimal Timing of HIV Therapy after Cryptococcal Meningitis
-
批准号:8101976
-
项目类别:
-
资助金额:$172.21万
-
财政年份:2010
-
负责人:David R Boulware
-
依托单位:
海外基金