Platform Trial For Cryptococcal Meningitis (PLATFORM-CM)

Официальное название

Platform Trial For Cryptococcal Meningitis

Обзор

Cryptococcal meningitis is a fungal infection that causes a severe syndrome of meningitis that is 100% fatal without antifungal therapy. Even with antifungal therapy, mortality rates remain high, especially in low and middle income countries where the ongoing HIV/AIDS pandemic increases the risk of cryptococcosis among persons living with HIV infection. The combination of amphotericin and flucytosine (5-FC) has been the mainstay of therapy for the initial management of cryptococcal meningitis for 4 decades. Indeed, the effective delivery of these first line therapy in Africa can lower mortality to 25%. However, several challenges exist. First, even while 5-FC is included on the WHO list of essential medicines, the availability of 5-FC worldwide is limited. Second, liposomal amphotericin (Ambisome ®) is currently available from a single source supplier, creating risk. Third, current therapies have substantial toxicity. Lastly, with widespread agricultural fungicide use of azoles, the median fluconazole minimum inhibitory concentration (MIC50 ) for Cryptococcus has doubled since 2013. Globally, new or improved antifungals are needed for cryptococcal meningitis, particularly those which have less toxicity, greater efficacy, a prolonged half-life, and minimal drug-drug interactions. As multiple new antifungal medicines are on the horizon, this platform trial utilizes a master protocol to investigate, multiple antifungal regimens using standardized eligibility criteria, standardized study schedule of events, and standardized contemporary endpoints.

Вмешательства

• Препарат Standard of care
  2022 WHO First Line Induction Therapy: 1. Liposomal Amphotericin B 10mg/kg IV given once 2. Flucytosine 100mg/kg/day for 14 days in divided doses 3. Fluconazole 1200mg/day for 14 days Consolidation Therapy: Fluconazole 800mg/day from 2 to 10 weeks Secondary Prophylaxis: Fluconazole 200mg/day through 1 year minimum
• Препарат Oteseconazole - antifungal therapy 1
  Oteseconazole, is an azole metalloenzyme inhibitor targeting the fungal sterol, 14α demethylase (CYP51) * Loading doses of oral Oteseconazole 600 mg twice daily for 10 days, then 600 mg oteseconazole weekly on weeks 3, 4, 5, and 6. * Liposomal Amphotericin B 10 mg/kg IV once. * No fluconazole or 5FC to be given.
• Препарат Turletricin injection - antifungal therapy 2
  SF001 2.0 mg/kg IV administered on day 1, followed by 1.5 mg/kg on day 8 with Fluconazole 1200mg/day and flucytosine 100mg/day in divided doses x 14 days
• Препарат Turletricin Injection - antifungal therapy 3
  SF001 3.0 mg/kg IV administered on day 1, 8, and 15 with fluconazole 1200mg/day and flucytosine 100mg/day in divided doses x 14 days
• Препарат Oteseconazole with Flucytosine - antifungal therapy 4
  Oteseconazole, is an azole metalloenzyme inhibitor targeting the fungal sterol, 14α demethylase (CYP51) ● Loading doses of oral Oteseconazole 600 mg twice daily for 12 days, then 600 mg oteseconazole weekly on weeks 3 to 12. ● Liposomal Amphotericin B 10 mg/kg IV once. ● Flucytosine 100mg/kg given for 7 days.

Первичные конечные точки

• Rate of cerebrospinal fluid (CSF) Cryptococcus clearance (Early Fungicidal Activity, or EFA) [Срок оценки: 2 weeks]
• All-cause mortality [Срок оценки: 2 weeks]

Вторичные конечные точки (9)

• Desirability of Outcome Response (DOOR) as ordinal ranked maximum score tested by Win Ratio. [Срок оценки: 18 weeks]
• Survival time through 18 weeks without Cryptococcus culture-positive relapse of meningitis [Срок оценки: 18 weeks]
• CSF culture sterility (cumulative incidence over 18 weeks) [Срок оценки: 18 weeks]
• 18-week survival time [Срок оценки: 18 weeks]
• Use of rescue/additional IV amphotericin beyond scheduled use [Срок оценки: 18 weeks]
• Modified Rankin score on functional status at 18 weeks [Срок оценки: 18 weeks]
• Incidence of laboratory abnormalities by Grade 1-5 [Срок оценки: 10 weeks]
• Incidence of serious adverse events [Срок оценки: 18 weeks]
• Incidence of study drug discontinuation or interruption >1 day due to toxicity, by adverse event grade. [Срок оценки: 10 weeks]

Критерии участия

Критерии включения

• CSF cryptococcal antigen (CrAg) positive meningitis
• Living with HIV
• Ability and willingness to provide informed consent
• Willing to receive protocol-specified lumbar punctures
• Age >= 18 years
• Female participants of childbearing potential who are participating in sexual activity that could lead to pregnancy must agree to use reliable forms of contraception (duration will be indicated in each Trial Appendix).

Критерии исключения

• Received 3 or more doses of antifungal therapy for meningitis within last 30 days
• Inability to take enteral (oral or nasogastric) medicine
• Cannot or unlikely to attend regular clinic visits
• Receiving chemotherapy or corticosteroids
• Receiving hemodialysis or known liver cirrhosis
• Suspected Paradoxical immune reconstitution inflammatory syndrome (IRIS)
• Pregnancy or breastfeeding
• Previous administration of investigational study drug
• Any condition for which participation would not be in the best interest of the participant or that could limit protocol specified assessments
• Trial Appendix study-drug specific eligibility criteria

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Простое слепое

Основная цель

Лечение

Центры проведения

Uganda · 2 центра

• Infectious Diseases Institute — Kampala
• Mbarara University of Science and Technology — Mbarara

Идентификаторы

NCT: NCT06666322 · IDIM-2024-32879

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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