BENDITA BEnznidazole New Doses Improved Treatment and Associations

• Register: ClinicalTrials.gov
• Last refreshed on: 8 January 2018
• Main ID: NCT03378661
• Date of registration: 23/11/2017
• Prospective Registration: No
• Primary sponsor: Drugs for Neglected Diseases
• Public title: BENDITA BEnznidazole New Doses Improved Treatment and Associations BENDITA
• Scientific title: Phase 2 Randomized, Multicenter, Safety and Efficacy Trial to Evaluate Different Oral Benznidazole Monotherapy and Benznidazole/E1224 Combination Regimens for the Treatment of Adult Patients With Chronic Indeterminate Chagas Disease
• Date of first enrolment: November 30, 2016
• Target sample size: 210
• Recruitment status: Active, not recruiting
• URL: https://clinicaltrials.gov/show/NCT03378661
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor).
• Phase: Phase 2

Countries of recruitment

Bolivia

Contacts

• Name: Joaquim Gascón, PhD
• Affiliation: Centro de Salud Internacional, Hospital Clínico de Barcelona CRESIB - Centre de Recerca en Salut Internacional de Barcelona Barcelona, España.

• Name: Faustino Torrico, PhD
• Affiliation: Plataforma de Atención Integral de Pacientes con Enfermedad de Chagas. Cochabamba, Bolivia.

Key inclusion & exclusion criteria

Screening criteria

- Signed, written informed consent form

- Age >18 to <50 years

- Weight >50 kg to <80 kg

- Diagnosis of T. cruzi infection by: Conventional serology (a minimum of two positive
tests [Conventional ELISA, Recombinant Elisa and/or Indirect Immunofluorescence
(IIF)])

- Ability to comply with all protocol specified tests and visits and have a permanent
address

- Patients must be residents of areas free of vectorial transmission (Triatoma
infestans). For this protocol, it will be accepted the status of Vectorial
Transmission Interruption or Consolidation as per the definition of PAHO/WHO, or the
Local Health Program.

- No signs and/or symptoms of the chronic cardiac and/or digestive form of CD

- 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 BZN (according to the Summary of Product
Characteristics) and E1224 (according to the Investigator's Brochure) Note: The
contraindications described for Benznidazole and E1224 are essentially
hypersensitivity to the active ingredient or any excipient. In the case of hepatic or
renal impairment or blood dyscrasia, the medication should only be administered under
strict medical supervision. During all the treatment period, the blood count will be
monitored, with special attention to leucocytes. Subjects will be indicated about the
need of no alcohol intake.

- No history of hypersensitivity, allergic, or serious adverse reactions to any of the
"azoles" compound, and/or its components

- No history of CD treatment with BZN or NFX at any time in the past

- No history of systemic treatment with itraconazole, ketoconazole, posaconazole,
isavuconazole, or allopurinol in the past

- No history of alcohol abuse or any other drug addiction (as specified in the Study
Manual of Operations)

- No condition that prevents patient from taking oral medication

- No concomitant or anticipated use of drugs that are either sensitive CYP3A4 substrates
and/or extensively metabolized by CYP3A4 with a narrow therapeutic range (as per
Appendix 2)

- No medical history of Familial Short QT syndrome or concomitant therapy with
medications that can shorten the QT interval (as per Appendix 2)

- No family history of sudden death

- No family history of sudden infant death syndrome

Inclusion criteria

Following the screening period, patients must 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 and/or IIF)

- Women in reproductive age must have a negative serum pregnancy test at screening, must
not be breastfeeding, and must use a double barrier method of contraception to avoid
pregnancy throughout a clinical trial and for 3 months after completion of the trial,
in such a manner that the risk of pregnancy is minimized especially during exposure to
treatment. Women who are using oral, implanted, or injectable contraceptive hormones
or mechanical products such as an intrauterine device with a hormonal component are
required to use an additional barrier method of contraception for the time period
specified.

- Normal EKG (PR =200 msec, QRS <120 msec, and QTc =350 msec and =450 msec interval
durations in males and QTc =470 msec in women) at screening.

Exclusion criteria

The presence of any of the following will exclude a patient from trial randomization:

- Signs and/or symptoms of chronic cardiac and/or digestive form of CD

- History of cardiomyopathy, heart failure, or ventricular arrhythmia.

- History of digestive surgery or mega syndromes.

- 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 disease requiring medical treatment).

- Laboratory test values considered clinically significant or out of the allowable range
at selection period as follows:

- Total 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)

- GGT must be within the normal range up to 2x ULN.

- Fasting glucose must be within the normal range

- Electrolytes (Ca, Mg, K) must be within the normal range

- 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 the
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 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 judgment
will decide if the patient is eligible or not for trial randomization.

- Any condition that prevents the patient from taking oral medication

- Patients with history of allergy (serious or not), allergic skin rash, asthma,
intolerance, sensitivity or photosensitivity to any drug

- Patients with any contra-indication (known hypersensitivity) to any nitroimidazoles,
e.g. metronidazole.

- Any concomitant use of allopurinol, antimicrobial, or anti-parasitic agents.

- Any planned surgery likely to interfere with the trial conduction and/or treatment
evaluation

- Unlikely to c


Age minimum: 18 Years
Age maximum: 50 Years
Gender: All

Health Condition(s) or Problem(s) studied

Chagas Disease

Intervention(s)

Drug: E1224

Drug: E1224 Placebo

Drug: Benznidazole

Drug: Benznidazole Placebo

Primary Outcome(s)

Parasitological response as determined by serial negative qualitative PCR results (3 negative PCR results, from 3 samples to be collected in the same day) at EOT and sustained parasitological clearance until 6 months follow-up. [Time Frame: From the end of the treatment period up to 6 months.]

Secondary Outcome(s)

Severity of Adverse Events (AEs) [Time Frame: Through study completion, i.e up to 12 months.]

Sustained parasitological clearance at 12 weeks and 12 months of follow-up [Time Frame: From the end of the treatment period up to 12 months.]

Serological response by conventional serology assessed at 12 months of follow up and non-conventional serology assessed at W12, 4, 6, and 12 months of follow up. (changes in titters over time) [Time Frame: From the end of the treatment period up to 12 months.]

Parasite clearance as measured by qualitative PCR [Time Frame: Weeks 1, 2, 3, 4, 6, 10, 12, and at 4, 6, and 12 months follow-up]

Change in parasite load over time assessed as measured by quantitative PCR [Time Frame: Weeks 1, 2, 3, 4, 6, 10, 12, and at 4, 6, and 12 months follow-up.]

Incidence of Adverse Events (AEs) [Time Frame: Through study completion, i.e up to 12 months.]

Incidence of Serious Adverse Events (SAEs) and/or adverse events leading to treatment discontinuation [Time Frame: Through study completion, i.e up to 12 months]

Secondary ID(s)

DNDi-CH-E1224-003

Source(s) of Monetary Support

Please refer to primary and secondary sponsors