## Protocol Section
### Identification Module
**NCT ID:** NCT06414512

**Brief Title:** Optimizing the Dose of Flucytosine for the Treatment of Cryptococcal Meningitis

**Official Title:** Optimizing the Dose of Flucytosine for the Treatment of Cryptococcal Meningitis

#### Organization Study ID Info
**ID:** STUDY00017800
#### Organization
**Class:** OTHER
**Full Name:** University of Minnesota
### Status Module
#### Completion Date
**Date:** 2024-09-01

**Type:** ESTIMATED

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2024-05-16

**Type:** ACTUAL

**Last Update Submit Date:** 2024-05-13

**Overall Status:** RECRUITING

#### Primary Completion Date
**Date:** 2024-09-01

**Type:** ESTIMATED

#### Start Date
**Date:** 2024-04-09

**Type:** ACTUAL

**Status Verified Date:** 2024-05

#### Study First Post Date
**Date:** 2024-05-16
**Type:** ACTUAL
**Study First Submit Date:** 2024-05-07
**Study First Submit QC Date:** 2024-05-13
### Sponsor Collaborators Module

#### Lead Sponsor

**Class:** OTHER

**Name:** University of Minnesota

#### Responsible Party

**Type:** SPONSOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** False

**Is US Export:** False

### Description Module

**Brief Summary:** Cryptococcal meningitis (CM) 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 Africa where the ongoing HIV/AIDS pandemic leads to higher prevalence of cryptococcosis. Combination of amphotericin and flucytosine (5-FC) is the mainstay of therapy for the initial management of CM. Indeed, it has even been shown that effective delivery of these therapies in Africa can lower mortality rates by 90%.

This is a prospective open-label trial to compare the efficacy and safety of lower doses of 5FC during induction therapy to historical controls with standard 5FC dosing. Participants in the trial will receive 60mg/kg/day of 5-FC in 3 divided doses for 10 days. Single-dose liposomal amphotericin (10mg/kg) is preferred, if available. Amphotericin B 0.7-1.0 mg/kg/day may be used if needed. Historical controls drawn from the AMBITION trial will be used as a comparison group, selected weighted by inclusion/exclusion criteria, baseline characteristics and therapies received. Induction therapy for control group participants followed the 2018 WHO cryptococcal guidelines with 7 days of 5-FC 100mg/kg/day and 7 days of IV Amphotericin deoxycholate followed by 1200mg fluconazole/day for 7 days. The intervention group received single- dose liposomal amphotericin plus 5-FC and fluconazole 1200 mg/day.

All participants will receive fluconazole 1200mg/day during consolidation therapy from day 1 to 14 then 800mg/day from day 15 to 10 weeks, and 200mg/day after 10 weeks. All participants will receive lumbar punctures at diagnosis, day 3, day 5-7, day 10-14, and additionally as required for control of intracranial pressure and documentation of CSF sterilization. Controls from Ambition will be matched for the same LP windows. Therapeutic LPs conducted during the first week have a \~70% relative survival benefit.

### Conditions Module

**Conditions:**

- Cryptococcal Meningitis

### Design Module

#### Design Info

**Allocation:** NA

**Intervention Model:** PARALLEL

**Intervention Model Description:** Prospective, open-label trial to compare the efficacy and safety of lower doses of 5FC during induction therapy to historical controls with standard 5FC dosing. Historical controls drawn from the AMBITION trial will be used as a comparison group, selected weighted by inclusion/exclusion criteria, baseline characteristics and therapies received.

##### Masking Info

**Masking:** NONE

**Primary Purpose:** TREATMENT

#### Enrollment Info

**Count:** 36

**Type:** ESTIMATED

**Phases:**

- PHASE2

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** Historical controls drawn from the AMBITION trial will be used as a comparison group, selected weighted by inclusion/exclusion criteria, baseline characteristics and therapies received.

**Intervention Names:**

- Drug: AMBITION trial control

**Label:** control

**Type:** ACTIVE_COMPARATOR

#### Arm Group 2

**Description:** HIV-infected persons in Uganda with cryptococcal meningitis

**Intervention Names:**

- Drug: Flucytosine

**Label:** Low Dose Flucytosine

**Type:** EXPERIMENTAL

### Interventions

#### Intervention 1

**Arm Group Labels:**

- control

**Description:** Induction therapy for control group participants followed the 2018 WHO cryptococcal guidelines with 7 days of 5-FC 100mg/kg/day and 7 days of IV Amphotericin deoxycholate followed by 1200mg fluconazole/day for 7 days.

**Name:** AMBITION trial control

**Type:** DRUG

#### Intervention 2

**Arm Group Labels:**

- Low Dose Flucytosine

**Description:** Participants in the trial will receive 60mg/kg/day of 5-FC in 3 divided doses for 10 days. Single-dose liposomal amphotericin (10mg/kg) is preferred, if available. Amphotericin B 0.7-1.0 mg/kg/day may be used if needed.

**Name:** Flucytosine

**Type:** DRUG

### Outcomes Module

#### Primary Outcomes

**Description:** quantified by the change of log 10 Cryptococcus CFU/mL CSF/day as measured by serial quantitative CSF fungal cultures over \~2 weeks

**Measure:** Rate of CSF Cryptococcus clearance (Early Fungicidal Activity, or EFA)

**Time Frame:** 2 weeks

#### Secondary Outcomes

**Measure:** CSF culture sterility cumulative incidence over 18 weeks

**Time Frame:** 18 weeks

**Measure:** 18-week survival time

**Time Frame:** 18 weeks

### Eligibility Module

**Eligibility Criteria:** Inclusion Criteria:

* CSF cryptococcal antigen (CrAg) positive meningitis
* Ability and willingness to provide informed consent
* Willing to receive protocol-specified lumbar punctures

Exclusion Criteria:

* Age \<18 years
* Inability to take enteral (oral or nasogastric) medicine
* Cannot or unlikely to attend regular clinic visits
* Receiving chemotherapy or corticosteroids
* Suspected Paradoxical immune reconstitution inflammatory syndrome (IRIS)
* Pregnancy or breastfeeding
* CrCl \< 20 mL/minute
* Absolute neutrophil count \<500 x10 6 cells/L
* Thrombocytopenia \< 50,000 x 10 6 cells/L
* Patients with prior 5-flucytosine exposure \>3 days in the 12 months prior to enrollment
* Any condition for which participation would not be in the best interest of the participant or that could limit protocol specified assessments.

**Minimum Age:** 18 Years

**Sex:** ALL

**Standard Ages:**

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Central Contacts

**Contact 1:**

**Email:** coat.trial@gmail.com

**Name:** David Boulware

**Role:** CONTACT

#### Locations

**Location 1:**

**City:** Kampala

**Contacts:**

***Contact 1:***

- **Email:** coat.trial@gmail.com

- **Name:** David Boulware

- **Role:** CONTACT

**Country:** Uganda

**Facility:** Infectious Disease Institute, Mulago Hospital Complex

**Status:** RECRUITING

**Zip:** 22418

**Location 2:**

**City:** Mbarara

**Contacts:**

***Contact 1:***

- **Email:** coat.trial@gmail.com

- **Name:** David Boulware

- **Role:** CONTACT

**Country:** Uganda

**Facility:** Mbarara University of Science and Technology

**Status:** RECRUITING

**Zip:** 1410

#### Overall Officials

**Official 1:**

**Affiliation:** University of Minnesota

**Name:** David B Meya

**Role:** PRINCIPAL_INVESTIGATOR

**Official 2:**

**Affiliation:** University of Minnesota

**Name:** David R Boulware

**Role:** PRINCIPAL_INVESTIGATOR

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000090862

- Term: Neuroinflammatory Diseases

- ID: D000009422

- Term: Nervous System Diseases

- ID: D000016921

- Term: Meningitis, Fungal

- ID: D000020314

- Term: Central Nervous System Fungal Infections

- ID: D000009181

- Term: Mycoses

- ID: D000001423

- Term: Bacterial Infections and Mycoses

- ID: D000007239

- Term: Infections

- ID: D000003453

- Term: Cryptococcosis

- ID: D000002494

- Term: Central Nervous System Infections

- ID: D000002493

- Term: Central Nervous System Diseases

### Condition Browse Module - Browse Branches

- Abbrev: BC01

- Name: Infections

- Abbrev: BC10

- Name: Nervous System Diseases

- Abbrev: All

- Name: All Conditions

- Abbrev: BC23

- Name: Symptoms and General Pathology

- Abbrev: Rare

- Name: Rare Diseases

### Condition Browse Module - Browse Leaves

- ID: M19263

- Name: Meningitis, Cryptococcal

- Relevance: HIGH

- As Found: Cryptococcal Meningitis

- ID: M11564

- Name: Meningitis

- Relevance: HIGH

- As Found: Meningitis

- ID: M2803

- Name: Neuroinflammatory Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M19265

- Name: Meningitis, Fungal

- Relevance: LOW

- As Found: Unknown

- ID: M10283

- Name: Infections

- Relevance: LOW

- As Found: Unknown

- ID: M12136

- Name: Mycoses

- Relevance: LOW

- As Found: Unknown

- ID: M6368

- Name: Communicable Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M22126

- Name: Central Nervous System Fungal Infections

- Relevance: LOW

- As Found: Unknown

- ID: M4722

- Name: Bacterial Infections

- Relevance: LOW

- As Found: Unknown

- ID: M4721

- Name: Bacterial Infections and Mycoses

- Relevance: LOW

- As Found: Unknown

- ID: M6664

- Name: Cryptococcosis

- Relevance: LOW

- As Found: Unknown

- ID: M5743

- Name: Central Nervous System Infections

- Relevance: LOW

- As Found: Unknown

- ID: M5742

- Name: Central Nervous System Diseases

- Relevance: LOW

- As Found: Unknown

- ID: T1668

- Name: Cryptococcosis

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000016919

- Term: Meningitis, Cryptococcal

- ID: D000008581

- Term: Meningitis

### Intervention Browse Module - Ancestors

- ID: D000000935

- Term: Antifungal Agents

- ID: D000000890

- Term: Anti-Infective Agents

- ID: D000000963

- Term: Antimetabolites

- ID: D000045504

- Term: Molecular Mechanisms of Pharmacological Action

### Intervention Browse Module - Browse Branches

- Abbrev: Infe

- Name: Anti-Infective Agents

- Abbrev: All

- Name: All Drugs and Chemicals

- Abbrev: Gast

- Name: Gastrointestinal Agents

### Intervention Browse Module - Browse Leaves

- ID: M8565

- Name: Flucytosine

- Relevance: HIGH

- As Found: Bad

- ID: M4002

- Name: Amphotericin B

- Relevance: LOW

- As Found: Unknown

- ID: M255436

- Name: Liposomal amphotericin B

- Relevance: LOW

- As Found: Unknown

- ID: M18296

- Name: Fluconazole

- Relevance: LOW

- As Found: Unknown

- ID: M7036

- Name: Deoxycholic Acid

- Relevance: LOW

- As Found: Unknown

- ID: M6252

- Name: Clotrimazole

- Relevance: LOW

- As Found: Unknown

- ID: M11796

- Name: Miconazole

- Relevance: LOW

- As Found: Unknown

- ID: M4254

- Name: Antifungal Agents

- Relevance: LOW

- As Found: Unknown

- ID: M4214

- Name: Anti-Infective Agents

- Relevance: LOW

- As Found: Unknown

- ID: M4281

- Name: Antimetabolites

- Relevance: LOW

- As Found: Unknown

### Intervention Browse Module - Meshes

- ID: D000005437

- Term: Flucytosine

### Misc Info Module

- Version Holder: 2024-05-31
