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Pharmacokinetic Drug-Drug Interaction Study

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ClinicalTrials.gov Identifier: NCT03892213
Recruitment Status : Completed
First Posted : March 27, 2019
Last Update Posted : March 27, 2019
Sponsor:
Collaborator:
PHINC DEVELOPMENT
Information provided by (Responsible Party):
Drugs for Neglected Diseases

Brief Summary:
The purpose of this study is to determine whether benznidazole and E1224 should be administered concomitantly in patients with Chagas Disease as not enough data are available. This study aims to assess cross interactions of these two compounds.

Condition or disease Intervention/treatment Phase
Chagas Disease Drug: Benznidazole Drug: E1224 Phase 1

Detailed Description:

Benznidazole and E1224 are intended to be administered concomitantly in patients with Chagas disease. Thus, an in vivo interaction study in healthy volunteers may be justified as the two drugs are intended to be administered concomitantly in patients and no in vivo nor in vitro data are available.

In addition both interactions (potential for benznidazole to interact on the pharmacokinetic (PK) of E1224 and potential for E1224 on the PK of benznidazole should be studied.

Benznidazole t1/2 is quite short (12 h) whereas E1224 t1/2 is very long (more than 200 h). Therefore it was chosen to study the interaction of E1224 at steady-state while interaction of benznidazole after single dose appears more appropriate instead of a classical randomized cross-over design.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 28 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1 Pharmacokinetic Drug-Drug Interaction Study of Benznidazole and E1224 in Healthy Male Volunteers
Study Start Date : October 2014
Actual Primary Completion Date : December 2014
Actual Study Completion Date : January 2015

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Benznidazole and E1224
Benznidazole and E1224
Drug: Benznidazole
Benznidazole single dose (2.5 mg/kg) at Day 1. Benznidazole single dose (2.5 mg/kg) at Day 9*. Benznidazole multiple dose (2.5 mg/kg twice daily) from Day 12* until Day 15.
Other Name: Abarax® (Benznidazole 100mg or 50mg).

Drug: E1224

E1224 multiple dose 400 mg loading dose once daily for 3 days (i.e. from Day 4 to Day 6 followed by maintenance dose 100mg once daily for 9 days (from Day 7 to Day15).

On Day 9 and from Day 12 to Day 15, E1224 and benznidazole will be given concomitantly.

Other Name: E1224 is a prodrug monolysine form of ravuconazole.




Primary Outcome Measures :
  1. Maximum serum concentration (Cmax) of Benznidazole [ Time Frame: Day 1 and day 9 ]
    BNZ PK parameter following single dose to investigate the possible drug-drug interaction between BNZ and E1224 through evaluation of the PK characteristics of both drugs when given alone or concomitantly.

  2. Time of occurrence of maximum plasma concentration (tmax) of Benznidazole [ Time Frame: Day 1 and day 9 ]
    BNZ PK parameter following single dose to investigate the possible drug-drug interaction between BNZ and E1224 through evaluation of the PK characteristics of both drugs when given alone or concomitantly.

  3. Area under the serum concentration versus time curve from time zero to the time (t) corresponding to the last quantifiable concentration (AUC 0-t) of Benznidazole [ Time Frame: Day 1 and day 9 ]
    BNZ PK parameter following single dose to investigate the possible drug-drug interaction between BNZ and E1224 through evaluation of the PK characteristics of both drugs when given alone or concomitantly.

  4. Area under the concentration-time curve from time zero to infinity with extrapolation of the terminal phase (AUC 0-∞) of Benznidazole [ Time Frame: Day 1 and day 9 ]
    BNZ PK parameter following single dose to investigate the possible drug-drug interaction between BNZ and E1224 through evaluation of the PK characteristics of both drugs when given alone or concomitantly.

  5. Terminal half-life (t1/2) of Benznidazole [ Time Frame: Day 1 and day 9 ]
    BNZ PK parameter following single dose to investigate the possible drug-drug interaction between BNZ and E1224 through evaluation of the PK characteristics of both drugs when given alone or concomitantly.

  6. Maximum serum concentration (Cmax) of Ravuconazole. [ Time Frame: Day 8 and day 15, day 6 (morning pre-dose), day 7 (morning pre-dose), day 8 (morning pre-dose), day 13 (morning pre-dose), day 14 (morning pre-dose), and day 15 (morning pre-dose) ]
    PK parameter of ravuconazole following multiple dose to investigate the possible drug-drug interaction between BNZ and E1224 (prodrug of ravuconazole) through evaluation of the PK characteristics of both drugs when given alone or concomitantly.

  7. Time of occurrence of maximum plasma concentration (tmax) of Ravuconazole. [ Time Frame: Day 8 and day 15, day 6 (morning pre-dose), day 7 (morning pre-dose), day 8 (morning pre-dose), day 13 (morning pre-dose), day 14 (morning pre-dose), and day 15 (morning pre-dose) ]
    PK parameter of ravuconazole following multiple dose to investigate the possible drug-drug interaction between BNZ and E1224 (prodrug of ravuconazole) through evaluation of the PK characteristics of both drugs when given alone or concomitantly.

  8. The area under the blood drug concentration vs. time curve from time zero (pre-dose) to 24 h post-dose (AUC 0-24) [ Time Frame: Day 8 and day 15, day 6 (morning pre-dose), day 7 (morning pre-dose), day 8 (morning pre-dose), day 13 (morning pre-dose), day 14 (morning pre-dose), and day 15 (morning pre-dose) ]
    PK parameter of ravuconazole following multiple dose to investigate the possible drug-drug interaction between BNZ and E1224 (prodrug of ravuconazole) through evaluation of the PK characteristics of both drugs when given alone or concomitantly.


Secondary Outcome Measures :
  1. Incidence of Adverse Events (AEs) [ Time Frame: Through study completion, i.e up to 22 days. ]
    Monitoring for the occurrence of adverse events (AEs)

  2. Clinically significant alterations in pulse rate [ Time Frame: Through study completion, i.e up to 22 days. ]
    Parameter to assess the safety and tolerability of multiple oral doses of BNZ and E1224 given in healthy male subjects.

  3. Clinically significant alterations in blood pressure [ Time Frame: Through study completion, i.e up to 22 days. ]
    Parameter to assess the safety and tolerability of multiple oral doses of BNZ and E1224 given in healthy male subjects.

  4. Clinically significant alterations in 12-lead ECG [ Time Frame: Through study completion, i.e up to 22 days. ]
    Parameter to assess the safety and tolerability of multiple oral doses of BNZ and E1224 given in healthy male subjects

  5. Clinically significant Haematology abnormalities (hemoglobin, RBC, hematocrit, MCV, MCH, MCHC, WBC, including differential, platelet counts) [ Time Frame: Day 1, Day 4, Day 7, Day 9, Day 10, Day 12, Day 13, Day 14 and Day 15 pre morning dose ]
    Parameter to assess the safety and tolerability of multiple oral doses of BNZ and E1224 given in healthy male subjects.

  6. Clinically significant Biochemistry abnormalities (albumin (ALB), ALP, ALT, AST, gamma-glutamyl transferase (GGT), chlorides (Cl-), creatinine, glucose (GLU), potassium (K+), sodium (Na+), total bilirubin (TBIL), total proteins (TP), Urea. [ Time Frame: Day 1, Day 4, Day 7, Day 9, Day 10, Day 12, Day 13, Day 14 and Day 15 pre morning dose ]
    Parameter to assess the safety and tolerability of multiple oral doses of BNZ and E1224 given in healthy male subjects.

  7. Clinically significant Urinalysis abnormalities (leukocytes, pH, proteins, urobilinogen, blood, nitrites, glucose, ketone bodies, bilirubin). [ Time Frame: Screening and day 22 ]
    Parameter to assess the safety and tolerability of multiple oral doses of BNZ and E1224 given in healthy male subjects.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 45 Years   (Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Male healthy volunteers 18 to 45 years of age;
  2. Light smokers (less than 5 cigarettes per day) or subjects who are non-smokers;
  3. Male subjects with a body weight of at least 50 kg and a body mass index (BMI) calculated as weight in kg/height (in m2) from 18 to 28 kg/m2 at screening;
  4. Able to communicate well with the Investigator and research staff and to comply with the requirements of the entire study;
  5. Provision of written informed consent to participate as shown by a signature on the volunteer consent form;

Exclusion Criteria:

  1. Who on direct questioning and physical examination have evidence of any clinically significant acute or chronic disease, including known or suspected HIV, hepatites B virus (HBV) or hepatites C virus (HCV) infection;
  2. Who has positive diagnosis of T. cruzi infection indicated by Conventional serology;
  3. With any clinically significant abnormality following review of pre-study laboratory tests, vital signs, full physical examination and 12-lead ECG;
  4. Who forfeit their freedom by administrative or legal award or who were under guardianship;
  5. Unwilling to give their informed consent;
  6. Who have a positive laboratory test for Hepatitis B surface antigen (HbsAg), or anti-HIV 1/2 or anti- HCV antibodies;
  7. Who have a history of allergy (serious or not), allergic skin rash, asthma, intolerance, sensitivity or photosensitivity to any drug;
  8. Who are known or suspected alcohol or drug abusers (more than 14 units of alcohol per week, one unit = 8 g or about 10 mL of pure alcohol);

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03892213


Locations
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Argentina
FP Clinical Pharma - Juncal 4484 - 3o piso
Buenos Aires, Argentina, C1425BAB
Sponsors and Collaborators
Drugs for Neglected Diseases
PHINC DEVELOPMENT
Investigators
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Study Chair: Isabela Ribeiro, MD Drugs for Neglected Diseases initiative
Principal Investigator: Ethel Feleder, MD F.P. Clinical Pharma Clinical Research Unit
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Responsible Party: Drugs for Neglected Diseases
ClinicalTrials.gov Identifier: NCT03892213    
Other Study ID Numbers: DNDi-CH-E1224-002
First Posted: March 27, 2019    Key Record Dates
Last Update Posted: March 27, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Keywords provided by Drugs for Neglected Diseases:
Chagas Disease
drug-drug interaction
benznidazole
E1224
pharmacokinetics
Additional relevant MeSH terms:
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Chagas Disease
Trypanosomiasis
Euglenozoa Infections
Protozoan Infections
Parasitic Diseases
Benzonidazole
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Trypanocidal Agents
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents