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Oral Fexinidazole Dosing Regimens for the Treatment of Adults With Chronic Indeterminate Chagas Disease (FEXI12)

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ClinicalTrials.gov Identifier: NCT03587766
Recruitment Status : Recruiting
First Posted : July 16, 2018
Last Update Posted : July 16, 2018
Sponsor:
Information provided by (Responsible Party):
Drugs for Neglected Diseases

Tracking Information
First Submitted Date  ICMJE April 27, 2018
First Posted Date  ICMJE July 16, 2018
Last Update Posted Date July 16, 2018
Actual Study Start Date  ICMJE November 13, 2017
Estimated Primary Completion Date December 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 3, 2018)
Incidence and severity of adverse events. [ Time Frame: 12 months ]
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: July 3, 2018)
  • Pharmacokinetic : measure of blood concentration of fexinidazole, fexinidazole sulfoxide and fexinidazole sulfone in order to determine AUC0-t values, for all dose levels. [ Time Frame: D0 (pre-dose), Day 1, Day 2, Day 3, and at steady-state phase (week 2-10). ]
  • Pharmacokinetic : measure of blood concentration of fexinidazole, fexinidazole sulfoxide and fexinidazole sulfone in order to determine Cmax values, for all dose levels. [ Time Frame: D0 (pre-dose), Day 1, Day 2, Day 3, and at steady-state phase (week 2-10). ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Oral Fexinidazole Dosing Regimens for the Treatment of Adults With Chronic Indeterminate Chagas Disease
Official Title  ICMJE Phase 2 Randomized, Multicenter, Double-blinded Safety and Efficacy Study to Evaluate Oral Fexinidazole Dosing Regimens for the Treatment of Adult Patients With Chronic Indeterminate Chagas Disease
Brief Summary This study focuses on the evaluation of low doses (600 and 1200 mg) and short treatment duration (at 3, 7 and 10 days) of fexinidazole (Fexi) to determine the minimal efficacious and safe dose for the treatment of adult patients with chronic indeterminate Chagas Disease (CD).
Detailed Description

Fexi anti-protozoal activity against T. cruzi has been demonstrated by various in vitro and in vivo studies.

Patients will be randomly assigned to receive one of three different treatment regimen arms containing either the active drug or matching placebo tablet

Following conclusion of 12 months of follow-up of DNDi-CH-FEXI-001 clinical trial, unblinded data review showed high sustained parasite clearance rates of FEXI even at the lowest dose tested (1200 mg 2 weeks), including in patients that received < 3days treatment.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
This study is designed as a double-blind, randomized, prospective, comparative, pharmacokinetic-pharmacodynamic, and proof-of-concept trial design, with three-parallel groups and historical placebo control in patients with chronic indeterminate Chagas Disease.
Masking: Double (Participant, Investigator)
Masking Description:
As the study is double-blinded, the patient, investigators, pharmacist(s) and DNDi study team members involved with the clinical trial implementation will remain blinded to treatment allocation for the duration of the clinical trial.
Primary Purpose: Treatment
Condition  ICMJE Chagas' Disease (Chronic) Nos
Intervention  ICMJE
  • Drug: Fexinidazole
    Drug: fexinidazole (FEXI)
    Other Name: FEXI
  • Drug: Placebo Oral Tablet
    Drug: fexinidazole
    Other Name: Placebo
Study Arms  ICMJE
  • Experimental: Group A
    Fexinidazole (FEXI) 600 mg x 10 days in a single daily dose orally (1 fexinidazole 600 mg tablet and 1 fexinidazole matching placebo oral tablet administered in a single daily dose) (total dose: 6.0 g).
    Interventions:
    • Drug: Fexinidazole
    • Drug: Placebo Oral Tablet
  • Experimental: Group B
    Fexinidazole (FEXI) 1200 mg x 3 days orally (2 fexinidazole 600 mg tablets administered in a single daily dose for 3 days), to be followed by matching placebo oral tablet for 7 days (2 fexinidazole matching placebo oral tablets administered once daily for 7 days) (total dose: 3.6 g).
    Interventions:
    • Drug: Fexinidazole
    • Drug: Placebo Oral Tablet
  • Experimental: Group C
    Fexinidazole (FEXI) 600 mg for 3 days, followed by 1200 mg in a single daily dose orally for 4 days (1 fexinidazole 600 mg tablet AND 1 fexinidazole matching placebo oral tablet administered in a single daily dose for 3 days, to be followed by 2 fexinidazole 600 mg tablets for 4 days), then followed by matching placebo oral tablet for 3 days (2 fexinidazole matching placebo tablets administered once daily for 3 days) (total dose: 6.6 g).
    Interventions:
    • Drug: Fexinidazole
    • Drug: Placebo Oral Tablet
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 3, 2018)
45
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2019
Estimated Primary Completion Date December 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Screening Criteria:

  • Signed, written informed consent form
  • Age >18 to < 60 years
  • Weight > 50 kg to < 90 kg
  • Diagnosis of T. cruzi infection by:
  • Conventional serology (a minimum of two positive tests [Conventional ELISA, Recombinant Elisa, Chemiluminescence Immunoassays and/or Indirect Immunofluorescence (IIF)]
  • Ability to comply with all protocol specified tests and visits and have a permanent address
  • No signs and/or symptoms of the chronic cardiac and/or digestive form of Chagas Disease (CD) (as per study operating procedures)
  • No personal history of mental disability or suicidal tendencies
  • No acute or chronic health conditions, that in the opinion of the PI, may interfere with the efficacy and/or safety evaluation of the trial drug (such as acute infections, history of HIV infection, liver, and renal disease requiring treatment)
  • No formal contraindication to FEXI (according to the latest available Investigator's Brochure)
  • No history of hypersensitivity, allergic, or serious adverse reactions to any of the "nitro-imidazoles" compound, and/or its components
  • No history of CD treatment with BZN, FEXI or Nifurtimox (NFX) at any time in the past
  • No history of alcohol abuse or any other drug addiction (as per Study Manual of Operations)
  • No condition that prevents patient from taking oral medication
  • No concomitant medication with drug known risk of Torsade de Pointe, according AZCERT Scientific Publications and Sudden Arrhythmia Death Syndromes Foundation (SADS Foundation) (https://www.crediblemeds.org/index.php/new-drug-list)
  • No family history of sudden death
  • No family history of sudden infant death syndrome

Inclusion Criteria:

Following the screening period, patients must also meet all of the following inclusion criteria to be eligible for randomization:

  • Confirmed diagnosis of T. cruzi infection by:
  • Serial qualitative PCR (three samples collected over a single day, at least one of which must be positive),

and

  • Conventional serology (a minimum of two positive tests must be positive, Conventional ELISA, Recombinant Elisa, Chemiluminescence immunoassays and/or IIF)
  • Women in reproductive age must have a negative serum pregnancy test at screening, must not be breastfeeding, must consistently use a highly effective contraceptive method until end of treatment and estimated FEXI, M1 and M2 clearance (total of 21 days). After this, contraception is no longer required.
  • Normal ECG (Heart rate: 50-100bpm; PR interval ≤200 msec, QRS complex ≤120 msec, and QT interval corrected for heart rate (QTc) ≥350msec and ≤450 msec interval durations) at screening
  • 24 hour Holter-monitoring with no clinically relevant arrythmias (defined as Ventricular Tachycardia (defined as >3 ventricular beats with >100bpm); Sustained Accelerated Idio-Ventricular rhythm (defined as >30 seconds duration and Heart Rate (HR): 50bpm<HR<100bpm); frequent Ventricular Premature Beats (10/hour); Atrial Fibrillation/flutter; Mobitz type 2 second degree AV block; High degree and complete AV block; Bradycardia episodes <40bpm)

Exclusion Criteria:

  • Signs and/or symptoms of chronic cardiac and/or digestive form of CD (as per Study Manual of Operations).
  • History of cardiomyopathy, heart failure, or ventricular arrhythmia.
  • History of digestive surgery or mega syndromes.
  • Personal history of mental disability or suicidal tendencies
  • Hospital Anxiety and Depression Scale (HADS - Appendix 1) self-assessment score >11 in each of the sub-scales. (Note: If HADS score >11, retesting would be allowed before after a minimum period of 15 days and referral to counseling/evaluation.)
  • Any other acute or chronic health conditions that, in the opinion of the PI, may interfere with the efficacy and/or safety evaluation of the trial drug (such as acute infections, history of HIV infection, diabetes, uncontrolled systolic/diastolic blood pressure, liver, and renal diseases requiring medical treatment).
  • Laboratory test values considered clinically significant or out of the allowable range at selection period as follows:

    • Total White Blood Count (WBC) must be within the normal range, with an acceptable margin of +/- 5% (3,800 - 10,500 / mm3).
    • Platelets must be within the normal range up to 550,000/mm3
    • Total bilirubin must be within the normal range
    • Transaminases (ALT and AST) must be within the normal range, with an acceptable margin of 25% above the upper limit of normality (ULN), < 1.25 x ULN.
    • Creatinine must be within an acceptable margin of 10% above the ULN, <1.10 x ULN.
    • Alkaline phosphatase must be within the normal range up to Grade 1 CTCAE (<,2.5 x ULN)
    • Gamma-glutamyl Transpeptidase (GGT) must be within the normal range up to 2x ULN.
    • Fasting glucose (minimum of 8 hours from latest meal) must be within the normal range
    • Electrolytes (Ca, Mg, K) must be within the normal range
    • Hepatitis screen must be negative for acute and/or chronic infection (Hepatitis A antibody, Imunoglobulina M (IgM); Hepatitis B surface Ag, Hepatitis B

If the results of the blood tests (hematology and biochemistry) are out of the ranges defined above, but within the limits of CTCAE (version 4.03) Grade 1, and this laboratory finding is considered as non-clinically significant, a new sample can be collected for a retest. Only one retest will be allowed within the screening period.

If the result of the retest is within the margins defined above, the Investigator will review the parameter(s) together with all other medical information available (medical history, clinical examinations, vital signs, etc.) and upon his/her medical judgement will decide if the patient is eligible or not for trial randomization.

Any condition that prevents the patient from taking oral medication.

  • Patients with any contra-indication (known hypersensitivity) to any nitroimidazoles, e.g. metronidazole
  • Patients with history of allergy (serious or not), allergic skin rash, asthma, intolerance, sensitivity or photosensitivity to any drug
  • Any concomitant use of allopurinol, antimicrobial, anti-parasitic agents, and/or of herbal medicines, food supplements and energetic drinks
  • Any concomitant medication with drug known risk of Torsade de Pointe, according AZCERT Scientific Publications and SADS Foundation (www.crediblemeds.org/index.php/new-drug-list)
  • Any planned surgery likely to interfere with the trial conduction and/or treatment evaluation
  • Unlikely to return for study visits, comply with study treatment and co-operate with the trial-related procedures.
  • Any previous participation in any clinical trial for Chagas Disease treatment evaluation
  • Participation in another trial at the same time or within 3 months prior to selection (according to local regulations).
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 60 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Sérgio S Estani, MD +55 21 25290439 ssosa@dndi.org
Contact: Fabiana Barreira, MD +55 21 25290416 fbarreira@dndi.org
Listed Location Countries  ICMJE Spain
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03587766
Other Study ID Numbers  ICMJE DNDi-FEX-12-CH
2016‐004905‐15 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Not yet decided how Individual Participant Data (IPD) will be shared, This action is under internal review within DNDi.
Responsible Party Drugs for Neglected Diseases
Study Sponsor  ICMJE Drugs for Neglected Diseases
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Joaquim Gascón, MD Centro de Salud Internacional, Hospital Clínico de Barcelona ISGlobal - Barcelona Institute for Global Health
PRS Account Drugs for Neglected Diseases
Verification Date July 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP