Study of Rezafungin Compared to Caspofungin in Subjects With Candidemia and/or Invasive Candidiasis

Fungal Infection Clinical Trial

— ReSTORE  

Official title:

A Phase 3, Multicenter, Randomized, Double-blind Study of the Efficacy and Safety of Rezafungin for Injection vs. Intravenous Caspofungin Followed by Oral Fluconazole Step Down in the Treatment of Subjects With Candidemia and/or Invasive Candidiasis

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03667690
• Other study ID #: CD101.IV.3.05
• Status: Completed
• Phase: Phase 3
• Start date: October 7, 2018
• Est. completion date: October 7, 2021

Study information

• Verified date: December 2022
• Source: Cidara Therapeutics Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this pivotal study is to determine if intravenous Rezafungin is efficacious and safe in the treatment of candidemia and/or invasive candidiasis when compared to caspofungin (followed by optional oral fluconazole).

Description:

A Phase 3, multicenter, prospective, randomized, double-blind, efficacy and safety study of Rezafungin for Injection versus an active comparator regimen of caspofungin followed by optional oral fluconazole step-down therapy in subjects with candidemia and/or invasive candidiasis.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 199
• Est. completion date: October 7, 2021
• Est. primary completion date: October 7, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Willing and able to provide written informed consent. If the subject is unable to consent for himself/herself, a legally acceptable representative must provide informed consent on his/her behalf.

2. Males or females =18 years of age.

3. Established mycological diagnosis of candidemia and/or invasive candidiasis from a sample taken =4 days (96 hours) before randomization defined as

• =1 blood culture positive for yeast or Candida OR

• Positive test for Candida from a Sponsor-approved rapid in vitro diagnostic (IVD) OR

• Positive gram stain (or other method of direct microscopy) for yeast or positive culture for Candida spp. from a specimen obtained from a normally sterile site.

4. Presence of one or more systemic signs attributable to candidemia or invasive candidiasis appearing from =12 hours prior to the qualifying positive culture through time of randomization.

5. Willing to initiate or continue medical treatment to cure infections, including receipt of antibiotics and surgical procedures, if required.

6. Female subjects of childbearing potential (all female subjects between 18 years <2 years post-menopausal unless surgically sterile) must agree to and comply with using one barrier method (e.g., female condom with spermicide) plus one other highly effective method of birth control, or sexual abstinence while participating in this study. Male subjects must be vasectomized, abstain from sexual intercourse, or agree to use barrier contraception, and also agree not to donate sperm while participating in the study and for 90 days thereafter (and at least 120 days from the last dose of study drug).

7. For Candidemia only subjects, drawing of a set of blood cultures within 12 hours prior to randomization in the study. The result of these blood cultures is not required for inclusion in the study.

Exclusion Criteria:

1. Any of the following forms of invasive candidiasis at baseline:

1. Septic arthritis in a prosthetic joint (septic arthritis in a native joint is allowed)

2. Osteomyelitis

3. Endocarditis or myocarditis

4. Meningitis, endophthalmitis, chorioretinitis, or any central nervous system infection

5. Chronic disseminated candidiasis

6. Urinary tract candidiasis due to ascending Candida infection secondary to obstruction or surgical instrumentation of the urinary tract

2. Received systemic treatment with an antifungal agent at approved doses for treatment of candidemia for >48 hours (e.g., >2 doses of a once daily antifungal agent or >4 doses of a twice daily antifungal agent) =4 days (96 hours) before randomization

a. Exception: Receipt of antifungal therapy to which any Candida spp. isolated in culture is not susceptible

3. Alanine aminotransferase or aspartate aminotransferase levels >10-fold the upper limit of normal

4. Severe hepatic impairment in subjects with a history of chronic cirrhosis (Child-Pugh score >9)

5. Presence of an indwelling vascular catheter or device that cannot be removed or an abscess that cannot be drained and is likely to be the source of candidemia or invasive candidiasis

6. Known hypersensitivity to Rezafungin for Injection, caspofungin, any echinocandin, or to any of their excipients

7. Meets National Cancer Institute Common Terminology Criteria for Adverse Events, version 5, criteria for ataxia, tremor, motor neuropathy, or sensory neuropathy of Grade 2 or higher

8. History of severe ataxia, tremor, or neuropathy or a diagnosis of multiple sclerosis or a movement disorder (including Parkinson's Disease or Huntington's Disease)

9. Planned or ongoing therapy at Screening with a known neurotoxic medication

10. Previous participation in this or any previous rezafungin study

11. Current participation in another interventional treatment trial with an investigational agent

12. Recent use of an investigational medicinal product within 28 days of the first dose of study drug or presence of an investigational device at the time of screening.

13. Pregnant or lactating females

14. The Principal Investigator (PI) is of the opinion the subject should not participate in the study

Related Conditions & MeSH terms

• Candidemia
• Candidiasis
• Candidiasis, Invasive
• Fungal Infection
• Invasive Candidiases
• Mycoses

Intervention

Drug:
• Rezafungin for Injection
Intravenous antifungal therapy
• Caspofungin
Intravenous antifungal therapy
• Fluconazole
Oral antifungal therapy
• intravenous placebo
Normal saline
• oral placebo
Microcrystalline cellulose

Locations

Country	Name	City	State
Argentina	Alexander Fleming Specialized Medical Institute	Buenos Aires
Argentina	Allende Sanatorium	Córdoba
Argentina	Cordoba Private Hospital	Córdoba
Argentina	Mayo Private Sanatorium	Córdoba
Argentina	Italian Hospital of Mendoza	Mendoza
Australia	Monash Health	Clayton	Victoria
Australia	Alfred Health	Melbourne	Victoria
Australia	Peter MacCallum Cancer Centre	Melbourne	Victoria
Australia	Westmead Public Hospital	Northmead	New South Wales
Australia	Royal Melbourne Hospital (RMH)	Parkville	Victoria
Belgium	Brugmann University Hospital Center	Brussels
Belgium	Erasme Hospital	Brussels
Belgium	Saint Luc University Hospital	Brussels
Belgium	University Hospital Brussels	Brussels
Belgium	University Hospitals Leuven, Campus Gasthuisberg	Leuven
Bulgaria	Multiprofile Hospital for Active Treatment Puls	Blagoevgrad
Bulgaria	University Multiprofile Hospital for Active Treatment and Emergency Medicine N.I. Pirogov EAD	Sofia
Bulgaria	University Multiprofile Hospital for Active Treatment and Emergency Medicine N.I. Pirogov EAD, Sofia, Clinic of Purulent-Septic Surgery	Sofia
China	The First Affiliated Hospital of Bengbu Medical College	Bengbu	Anhui
China	The Second Xiangya Hospital of Central South University	Changsha	Hunan
China	West China Hospital, Sichuan University	Chengdu	Sichuan
China	Chongqing People's Hospital	Chongqing	Chongqing
China	Guangdong Provincial People's Hospital	Guangzhou	Guangdong
China	Guangzhou First People's Hospital	Guangzhou	Guangdong
China	The First Affiliated Hospital of Guangzhou Medical University	Guangzhou	Guangdong
China	The Second Hospital of Anhui Medical University	Hefei	Anhui
China	The Second People's Hospital of Hefei	Hefei	Anhui
China	Nanjing First Hospital	Nanjing	Jiangsu
China	Qingyuan People's Hospital	Qingyuan	Guangdong
China	Huashan Hospital Affiliated Fudan University	Shanghai
China	Shanghai Pulmonary Hospital	Shanghai
China	General Hospital of Tianjin Medical University	Tianjin
China	Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences	Tianjin
China	Zhongnan Hospital of Wuhan University	Wuhan	Hubei
China	Zibo Central Hospital	Zibo	Shandong
Colombia	CEQUIN Foundation Cardiomet	Armenia
Colombia	De La Costa Clinic Ltd.	Barranquilla
Colombia	University IPS - Leon XIII Clinic	Medellín
France	Amiens Picardie University Hospital - South	Amiens
France	Centre Hospitalier Victor Dupouy - Argenteuil	Argenteuil
France	Roger Salengro Hospital	Lille
France	Marseille University Hospital Center - North Hospital	Marseille
France	Hotel Dieu Hospital Nantes University Hospital Center	Nantes
France	Paris University Hospitals Center - Cochin Hospital	Paris
France	Saint-Louis Hospital	Paris
France	University Hospital Center of Poitiers	Poitiers
France	Civil Hospital of Strasbourg	Strasbourg
France	Tours University Hospital Center, Bretonneau Hospital	Tours
Germany	University Hospital Köln	Cologne
Germany	University Hospital Freiburg	Freiburg
Germany	Johannes Gutenberg University Medical Center	Mainz
Greece	General Hospital of Athens "Evangelismos"	Athens
Greece	General Hospital of Athens "Evangelismos", 5th Department of Internal Medicine and Infectious Diseases Unit	Athens
Greece	General Hospital of Athens "Laikon"	Athens
Greece	General Hospital of Athens "Laikon", Infectious Diseases Unit	Athens
Greece	General Hospital of Thessaloniki Ippokratio	Thessaloníki
Israel	Edith Wolfson Medical Center	H_olon
Israel	Bnai Zion Medical Center	Haifa
Israel	Lady Davis Carmel Medical Center	Haifa
Israel	Rambam Health Care Campus	Haifa
Israel	Hadassah Medical Center	Jerusalem
Israel	The Baruch Padeh Medical Center	Nazareth
Israel	Ziv Medical Center	Safed
Israel	The Tel Aviv Sourasky Medical Center	Tel Aviv
Israel	Chaim Sheba Medical Center	Tel Hashomer
Italy	Polyclinic S. Orsola-Malpighi, Dept. of Organ Impairment and Transplants	Bologna
Italy	ASST Large Metropolitan Hospital Niguarda, Infectious Diseases Department	Milan
Italy	University Hospital of Modena	Modena
Italy	University Polyclinic Hospital of Modena	Modena
Italy	University of Milano-Bicocca - San Gerardo Hospital	Monza
Italy	University Polyclinic Hospital "Paolo Giaccone" Palermo, Infectious Disease Department, ICU	Palermo
Italy	University Polyclinic Foundation Agostino Gemelli - IRCCS	Rome
Italy	Integrated University Health Authority of Trieste	Trieste
Italy	Integrated University Hospital "Santa Maria della Misericordia" of Udine	Udine
Korea, Republic of	Dong-A University Hospital	Busan
Korea, Republic of	Chung-Ang University Hospital	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Severance Hospital, Yonsei University Health System	Seoul
Korea, Republic of	Ajou University Hospital	Suwon
Korea, Republic of	Wonju Severance Christian Hospital	Wonju	Gangwon-do
Singapore	National University Hospital	Singapore
Singapore	Tan Tock Seng Hospital	Singapore
Spain	University Hospital Germans Trias i Pujol	Badalona
Spain	University Hospital Cruces	Baracaldo
Spain	Hospital Clinic of Barcelona	Barcelona
Spain	Hospital del Mar, Department of Infectious Diseases	Barcelona
Spain	Parc Tauli Health Corporation	Barcelona
Spain	University Hospital Vall d'Hebron (HUVH)	Barcelona
Spain	General University Hospital Gregorio Maranon	Madrid
Spain	La Paz University Hospital	Madrid
Spain	University Hospital Clinical San Carlos	Madrid
Spain	University Hospital Ramon y Cajal	Madrid
Spain	University Hospital Puerta de Hierro Majadahonda	Majadahonda
Spain	University Hospital Virgen Macarena	Sevilla
Spain	University and Polytechnic Hospital La Fe	Valencia
Taiwan	Kaohsiung Medical University Chung-Ho Memorial Hospital	Kaohsiung
Taiwan	China Medical University Hospital	Taichung
Taiwan	National Taiwan University Hospital	Taipei
Taiwan	Taipei Veterans General Hospital	Taipei
Taiwan	Linkou Chang Gung Memorial Hospital	Taoyuan City
Thailand	King Chulalongkorn Memorial Hospital	Bangkok
Thailand	Rajavithi Hospital	Bangkok
Thailand	Ramathibodi Hospital	Bangkok
Thailand	Siriraj Hospital	Bangkok
Thailand	Maharaj Nakorn Chiang Mai Hospital	Chiang Mai
Thailand	Srinagarind Hospital	Khon Kaen
Thailand	Thammasat University Hospital	Pathum Thani
Thailand	Songklanagarind Hospital	Songkhla
Turkey	Ankara University School of Medicine	Ankara
Turkey	Hacettepe University School of Medicine	Ankara
Turkey	Istanbul University School of Medicine	Istanbul
Turkey	Marmara University Pendik Training and Research Hospital	Istanbul
Turkey	Medipol Mega University Hospital	Istanbul
United States	Emory University Hospital	Atlanta	Georgia
United States	Augusta University	Augusta	Georgia
United States	Johns Hopkins	Baltimore	Maryland
United States	University of Alabama	Birmingham	Alabama
United States	Mecury Street Medical	Butte	Montana
United States	University of North Carolina	Chapel Hill	North Carolina
United States	Henry Ford Health System	Detroit	Michigan
United States	Duke University Medical Center	Durham	North Carolina
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	University of Minnesota	Minneapolis	Minnesota
United States	University of Pittsburgh Falk Medical Center	Pittsburgh	Pennsylvania
United States	Carilion Clinic	Roanoke	Virginia
United States	Mayo Clinic Hospital-Rochester	Rochester	Minnesota
United States	UC Davis	Sacramento	California
United States	Washington University St. Louis	Saint Louis	Missouri
United States	The University of Texas Health Science Center at San Antonio	San Antonio	Texas
United States	Baylor Scott and White Medical Center	Temple	Texas
United States	ID Clinical Research, Ltd.	Toledo	Ohio
United States	Reading Hospital and Medical Center	West Reading	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
Cidara Therapeutics Inc.

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Belgium,  Bulgaria,  China,  Colombia,  France,  Germany,  Greece,  Israel,  Italy,  Korea, Republic of,  Singapore,  Spain,  Taiwan,  Thailand,  Turkey, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	All-Cause Mortality (US FDA Only)	The number and percentage of subjects in each treatment group who are alive and deceased (or with missing data) in the mITT population.	Day 30 (-2 days)
Primary	Global Response as Assessed by Data Review Committee (EU European Medicines Agency [EMA] Only)	The number and percentage of subjects in each treatment group who have a global response of cure (clinical cure as assessed by the Investigator, radiological cure [for qualifying invasive candidiasis subjects at baseline], and mycological eradication, as confirmed by the Data Review Committee [DRC]), failure and indeterminate in the mITT population. A global response of cure is indicative of an efficacious outcome and the desired result, whereas a response of failure is indicative of a non-efficacious outcome and the undesired response. Indeterminate responses indicate there was not enough data obtained to determine if the response was cure or failure. Definitions for the global responses of cure, failure, and indeterminate are complex. Detailed definitions for the possible responses to this outcome measure type are provided in Table 7 (Global Response) of the clinical protocol.	Day 14 (±1 day)
Secondary	Global Response as Assessed by Data Review Committee (US FDA Only)	The number and percentage of subjects in each treatment group who have a global response of cure (clinical cure as assessed by the Investigator, radiological cure [for qualifying invasive candidiasis subjects at baseline], and mycological eradication, as confirmed by the Data Review Committee [DRC]), failure and indeterminate in the mITT population. A global response of cure is indicative of an efficacious outcome and the desired result, whereas a response of failure is indicative of a non-efficacious outcome and the undesired response. Indeterminate responses indicate there was not enough data obtained to determine if the response was cure or failure. Definitions for the global responses of cure, failure, and indeterminate are complex. Detailed definitions for the possible responses to this outcome measure type are provided in Table 7 (Global Response) of the clinical protocol.	Day 14 (±1 day)
Secondary	All-Cause Mortality (EU EMA Only)	The number and percentage of subjects in each treatment group who are alive and deceased (or with missing data) in the mITT population.	Day 30 (-2 days)
Secondary	Comparison of Global Response (as Assessed by the DRC) by Visit	The number and percentage of subjects in each treatment group who have a global response of cure (clinical cure as assessed by the Investigator, radiological cure [for qualifying invasive candidiasis subjects at baseline], and mycological eradication, as confirmed by the Data Review Committee [DRC]), failure and indeterminate in the mITT population. A global response of cure is indicative of an efficacious outcome and the desired result, whereas a response of failure is indicative of a non-efficacious outcome and the undesired response. Indeterminate responses indicate there was not enough data obtained to determine if the response was cure or failure. Definitions for the global responses of cure, failure, and indeterminate are complex. Detailed definitions for the possible responses to this outcome measure type are provided in Table 7 (Global Response) of the clinical protocol.	Day 5, Day 30 (-2 days), End of Treatment (EOT) (=2 days of last dose) and Follow-up (Days 52-59)
Secondary	Comparison of Mycological Eradication by Visit	The number and percentage of subjects in each treatment group who have a mycological response of eradication, failure, or indeterminate in the mITT population. A mycological response of eradication means clearance of objective evidence of infection and is indicative of an efficacious outcome and the desired result, whereas a response of failure is indicative of a non-efficacious outcome and the undesired response. Indeterminate responses indicate there was not enough data obtained to determine if the response was eradication or failure. Definitions for the mycological responses of eradication, failure, and indeterminate are complex. Detailed definitions for the possible responses to this outcome measure type are provided in Table 8 (Mycological Response) of the clinical protocol.; Note: Eradication includes both documented and presumed eradication.	Day 5, Day 14 (±1 day), Day 30 (-2 days), End of Treatment (EOT) (=2 days of last dose), and Follow-up (Days 52-59)
Secondary	Comparison of Investigators' Assessment of Clinical Response by Visit	The number and percentage of subjects in each treatment group for whom the Investigator determined a clinical response of cure, failure, or indeterminate in the mITT population. A clinical response of cure, as assessed by the Investigator, is indicative of an efficacious outcome and the desired result, whereas a response of failure is indicative of a non-efficacious outcome and the undesired response. Indeterminate responses indicate there was not enough data obtained to determine if the response was cure or failure. Definitions for the clinical responses of cure, failure, and indeterminate are complex. Detailed definitions for the possible responses to this outcome measure type are provided in Table 9 (Investigator's Assessment of Clinical Response) of the clinical protocol.	Day 5, Day 14 (±1 day), Day 30 (-2 days), End of Treatment (EOT) (=2 days of last dose), and Follow-up (Days 52-59)
Secondary	Comparison of Radiological Response by Investigator by Visit	The number and percentage of subjects with invasive candidiasis (documented by radiologic/imaging evidence at baseline) in each treatment group who have a radiological response (as assessed by the Investigator) of cure, failure, and indeterminate in the mITT population. A radiological response of cure is indicative of an efficacious outcome and the desired result, whereas a response of failure is indicative of a non-efficacious outcome and the undesired response. Indeterminate responses indicate there was not enough data obtained to determine if the response was cure or failure. Definitions for the radiological responses of cure, failure, and indeterminate are complex. Detailed definitions for the possible responses to this outcome measure type are provided in Table 10 (Radiological Response) of the clinical protocol.	Day 5, Day 14 (±1 day), Day 30 (-2 days), End of Treatment (EOT) (=2 days of last dose), and Follow-up (Days 52-59)
Secondary	Number of Subjects With Treatment-Emergent Adverse Events [Safety and Tolerability]	The number and percentage of subjects in each treatment group that experienced at least one treatment-emergent adverse event (TEAE) based on clinical chemistry, hematology and urine analysis laboratory test, vital sign, physical exams and electrocardiogram (ECG) abnormalities.; Notes: A subject with multiple adverse events (AEs) was counted only once. TEAE was defined as an AE that occurred during or after study drug administration and up through the Follow-up visit. The maximum severity and strongest relationship were counted for subjects with multiple events.	Day 1 through Follow-up Visit (Days 52-59)
Secondary	Evaluate Pharmacokinetics (Cmax)	Evaluate the maximum plasma concentration (Cmax) of rezafungin for injection.	Day 1, 10 minutes before the end of infusion
Secondary	Evaluate Pharmacokinetics (Cmin)	Evaluate the minimum plasma concentration (Cmin) of rezafungin for injection.	Day 8, pre-dose, within 30 minutes prior to the start of infusion
Secondary	Evaluate Pharmacokinetics (Cmin)	Evaluate the minimum plasma concentration (Cmin) of rezafungin for injection.	Day 15, pre-dose, within 30 minutes prior to the start of infusion
Secondary	Evaluate Pharmacokinetics (Cmin)	Evaluate the minimum plasma concentration (Cmin) of rezafungin for injection.	Day 22, pre-dose, within 30 minutes prior to the start of infusion