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

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.

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).