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Study Will Evaluate the Relative Bioavailability, Safety, and Tolerability of Single Doses of Nifurtimox 30 mg Tablets Exhibiting Different in Vitro Dissolution Characteristics, and to Evaluate the Relative Bioavailability of Nifurtimox 30 mg and 120 mg

Primary Purpose

Chagas Disease

Status
Completed
Phase
Phase 1
Locations
Argentina
Study Type
Interventional
Intervention
Nifurtimox (Lampit, BAYA2502)
Sponsored by
Bayer
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Chagas Disease focused on measuring Relative bioavailability, In vitro dissolution

Eligibility Criteria

18 Years - 45 Years (Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria

  • Women and men of reproductive potential must agree to use adequate contraception when sexually active. This applies for the time period between signing of the informed consent form and 12 weeks after the last administration of study drug. The definition of adequate contraception will be based on the judgment of the investigator and on local requirements. Acceptable methods of contraception include, but are not limited to: (i) condoms (male or female) with or without a spermicidal agent; (ii) diaphragm or cervical cap with spermicide; (iii) intra-uterine device; (iv) hormone-based contraception. Subjects must agree to utilize two reliable and acceptable methods of contraception simultaneously.
  • Women of childbearing potential with confirmed last menstrual period by anamnesis and negative serum pregnancy test (beta-human chorionic gonadotropin [βhCG]) at screening and negative urine pregnancy test (βhCG) at pre-dose of each treatment.
  • Women of non-childbearing potential, such as surgically sterile women with either written documentation of surgical sterility or negative serum pregnancy test (βhCG) at screening and negative urine pregnancy test (βhCG) at pre-dose of each treatment.
  • Male subjects who agree not to act as sperm donors for 12 weeks after last administration of study drug.
  • Age: 18 to 45 years (inclusive) at screening.
  • Body mass index (BMI): ≥18 and <29.9 kg/m².
  • Written informed consent must be provided before any study-specific tests or procedures are performed.
  • Male/female patient diagnosed with chronic Chagas' disease:
  • Previous diagnosis of acute or chronic Chagas' disease by a health clinic prior to screening for the study. The diagnosis of chronic Chagas' disease may be made by clinical findings, supported by antibody titers if available. If there is a known history of acute disease, it is preferable to have documentation of parasites on the blood smear, if available.

Exclusion Criteria

  • Incompletely cured pre-existing diseases (except chronic Chagas' disease without active GI condition) for which it can be assumed that the absorption, distribution, metabolism, elimination, and effects of the study drugs will not be normal.
  • Acute Chagas' disease. (During the acute phase, the parasite on a blood smear may be seen under a microscope. Different antibodies are present, depending on the course of the disease).
  • Known hypersensitivity to the study drug (active substance or excipients of the preparations)
  • Unstable or uncontrolled medical condition such as hypertension or diabetes, decompensated heart failure, GI conditions that would interfere with the absorption of the study drug (e.g. GI ulceration, peptic ulceration, GI bleeding, gastroesophageal reflux, or other GI disease affecting gastroesophageal junction), conditions that could potentially have an impact on drug metabolism or elimination (renal, hepatic such as known hepatic or biliary abnormalities), or any clinically relevant active infections in the opinion of the investigator within 4 weeks before the screening visit, e.g. clinically relevant history or presence of significant respiratory (e.g. interstitial lung disease), hematological, lymphatic, neurological, cardiovascular, psychiatric, musculoskeletal, genitourinary, immunological, metabolic (e.g. diabetes), and dermatological or connective tissue disease.
  • Use of systemic or topical medicines or substances which oppose the study objectives (including clinical treatment with nifurtimox and benznidazole) or which might influence them within 4 weeks before the first study drug administration, e.g. an investigational drug, any drug altering GI motility and/or gastric pH (e.g. antacids, anticholinergic, para-sympatholytics), any drug known to induce liver enzymes (e.g. dexamethasone, barbiturates, St. John's Wort [hypericum perforatum]), any drug known to inhibit liver enzymes (e.g. ketoconazole, macrolides).
  • Clinically relevant findings in the ECG such as a second- or third-degree atrioventricular block, prolongation of the QRS complex over 120 msec or of the QT interval over 450 msec using Bazett's formula (QTcB). (Clinically stable subjects with Chagas'-related heart disease and pacemaker in place for >1 year and evaluated by a cardiologist ≤6 months before the first dose of study drug will not be excluded.)
  • Systolic blood pressure <100 or >140 mmHg (after resting in supine position for a minimum of 3 minutes).
  • Diastolic blood pressure <50 or >90 mmHg (after resting in supine position for a minimum of 3 minutes).
  • Findings that would exclude the subject in the investigator's judgment, e.g. enlarged liver, irregular heartbeat, undiagnosed acute illness, and melanoma.
  • Positive pregnancy test.
  • Positive results for hepatitis B virus surface antigen (HBsAg), hepatitis C virus antibodies (anti-HCV), or human immunodeficiency virus antibodies (anti-HIV 1+2).
  • Positive urine drug screening..

Sites / Locations

  • FP Clinical Pharma

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

GRP1 - Assess relative bioavailability(3-way cross-over)

GRP2 - Assess relative bioavailability (2-way cross-over)

Arm Description

GROUP 1 (Treatments A, B, C) All 3 treatments in Group 1 consist of a dose of 120 mg nifurtimox (4 x 30 mg tablets). Participants received the 3 treatments in one of six treatment sequences under fed condition. Treatment A, dose administration with fast in vitro dissolution characteristics Treatment B, dose administration with medium in vitro dissolution characteristics Treatment C, dose administration with slow in vitro dissolution characteristics

GROUP 2 (Treatments D and E) Participants received the 2 treatments in one of two treatment sequences under fed condition. Treatment D, a single dose 30 mg nifurtimox dose with medium in vitro dissolution characteristics Treatment E, a single dose of 120 mg nifurtimox

Outcomes

Primary Outcome Measures

AUC(0-tlast) of nifurtimox
AUC(0-tlast):Area under the drug-concentration vs. time curve of nifurtimox from time 0 to the last data point
Cmax of nifurtimox
Cmax: Maximum observed drug concentration in measured matrix after single dose administration
AUC of nifurtimox
AUC: Area under the concentration versus time curve from zero to infinity after single (first) dose

Secondary Outcome Measures

Number of participants with adverse events
AUC divided by dose: AUC/D
AUC(0-tlast) divided by dose: AUC(0-tlast)/D
Cmax divided by dose: Cmax/D

Full Information

First Posted
November 9, 2017
Last Updated
December 11, 2019
Sponsor
Bayer
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1. Study Identification

Unique Protocol Identification Number
NCT03350295
Brief Title
Study Will Evaluate the Relative Bioavailability, Safety, and Tolerability of Single Doses of Nifurtimox 30 mg Tablets Exhibiting Different in Vitro Dissolution Characteristics, and to Evaluate the Relative Bioavailability of Nifurtimox 30 mg and 120 mg
Official Title
Open Label, Randomized, Single-dose, Cross-over Study to Evaluate the Relative Bioavailability, Safety, and Tolerability of Single Doses of Nifurtimox 30 mg Tablets Exhibiting Different in Vitro Dissolution Characteristics, and to Evaluate the Relative Bioavailability of Nifurtimox 30 mg and 120 mg Tablets, Administered to Adult Male and Female Patients With Chagas' Disease
Study Type
Interventional

2. Study Status

Record Verification Date
December 2019
Overall Recruitment Status
Completed
Study Start Date
June 14, 2018 (Actual)
Primary Completion Date
September 18, 2018 (Actual)
Study Completion Date
December 14, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Bayer

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
Study to assess the relative Bioavailability To assess the relative bioavailability of three formulations of nifurtimox 30 mg tablets exhibiting different in vitro dissolution profiles To assess the pharmacokinetics (PK) of nifurtimox To investigate the safety and tolerability of nifurtimox.
Detailed Description
Primary objective is to assess the relative bioavailability of three formulations of nifurtimox 30 mg tablets exhibiting different in vitro dissolution profiles (slow, medium, and fast, whereby "medium" represents the drug product currently used in clinical Phase 3 studies) under fed conditions in adult male and female patients with Chagas' disease. A secondary objective of the study is to assess the relative bioavailability of nifurtimox after a single oral dose of 30 mg and 120 mg To assess the pharmacokinetics (PK) of nifurtimox To investigate the safety and tolerability of nifurtimox..

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chagas Disease
Keywords
Relative bioavailability, In vitro dissolution

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Crossover Assignment
Model Description
Group 1 ( Treatment A,B,C - 3 way cross-over), Group 2 ( Treatment D, E - 2 way cross over)
Masking
None (Open Label)
Allocation
Randomized
Enrollment
48 (Actual)

8. Arms, Groups, and Interventions

Arm Title
GRP1 - Assess relative bioavailability(3-way cross-over)
Arm Type
Experimental
Arm Description
GROUP 1 (Treatments A, B, C) All 3 treatments in Group 1 consist of a dose of 120 mg nifurtimox (4 x 30 mg tablets). Participants received the 3 treatments in one of six treatment sequences under fed condition. Treatment A, dose administration with fast in vitro dissolution characteristics Treatment B, dose administration with medium in vitro dissolution characteristics Treatment C, dose administration with slow in vitro dissolution characteristics
Arm Title
GRP2 - Assess relative bioavailability (2-way cross-over)
Arm Type
Experimental
Arm Description
GROUP 2 (Treatments D and E) Participants received the 2 treatments in one of two treatment sequences under fed condition. Treatment D, a single dose 30 mg nifurtimox dose with medium in vitro dissolution characteristics Treatment E, a single dose of 120 mg nifurtimox
Intervention Type
Drug
Intervention Name(s)
Nifurtimox (Lampit, BAYA2502)
Intervention Description
Oral Intake of 4 x 30 mg nifurtimox tablets for treatment A-C; Oral Intake of 1 x 30 mg nifurtimox tablets for treatment D Oral intake of 1 x 120 mg nifurtimox tablet for treatment E
Primary Outcome Measure Information:
Title
AUC(0-tlast) of nifurtimox
Description
AUC(0-tlast):Area under the drug-concentration vs. time curve of nifurtimox from time 0 to the last data point
Time Frame
0, 15, 30, 45 min, 1, 1.5, 2, 2.5, 3, 4, 6, 8,12,15 hour
Title
Cmax of nifurtimox
Description
Cmax: Maximum observed drug concentration in measured matrix after single dose administration
Time Frame
0, 15, 30, 45 min, 1, 1.5, 2, 2.5, 3, 4, 6, 8,12,15 hour
Title
AUC of nifurtimox
Description
AUC: Area under the concentration versus time curve from zero to infinity after single (first) dose
Time Frame
0, 15, 30, 45 min, 1, 1.5, 2, 2.5, 3, 4, 6, 8,12,15 hour
Secondary Outcome Measure Information:
Title
Number of participants with adverse events
Time Frame
up to 8 weeks
Title
AUC divided by dose: AUC/D
Time Frame
0, 15, 30, 45 min, 1, 1.5, 2, 2.5, 3, 4, 6, 8,12,15 hour
Title
AUC(0-tlast) divided by dose: AUC(0-tlast)/D
Time Frame
0, 15, 30, 45 min, 1, 1.5, 2, 2.5, 3, 4, 6, 8,12,15 hour
Title
Cmax divided by dose: Cmax/D
Time Frame
0, 15, 30, 45 min, 1, 1.5, 2, 2.5, 3, 4, 6, 8,12,15 hour

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
45 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria Women and men of reproductive potential must agree to use adequate contraception when sexually active. This applies for the time period between signing of the informed consent form and 12 weeks after the last administration of study drug. The definition of adequate contraception will be based on the judgment of the investigator and on local requirements. Acceptable methods of contraception include, but are not limited to: (i) condoms (male or female) with or without a spermicidal agent; (ii) diaphragm or cervical cap with spermicide; (iii) intra-uterine device; (iv) hormone-based contraception. Subjects must agree to utilize two reliable and acceptable methods of contraception simultaneously. Women of childbearing potential with confirmed last menstrual period by anamnesis and negative serum pregnancy test (beta-human chorionic gonadotropin [βhCG]) at screening and negative urine pregnancy test (βhCG) at pre-dose of each treatment. Women of non-childbearing potential, such as surgically sterile women with either written documentation of surgical sterility or negative serum pregnancy test (βhCG) at screening and negative urine pregnancy test (βhCG) at pre-dose of each treatment. Male subjects who agree not to act as sperm donors for 12 weeks after last administration of study drug. Age: 18 to 45 years (inclusive) at screening. Body mass index (BMI): ≥18 and <29.9 kg/m². Written informed consent must be provided before any study-specific tests or procedures are performed. Male/female patient diagnosed with chronic Chagas' disease: Previous diagnosis of acute or chronic Chagas' disease by a health clinic prior to screening for the study. The diagnosis of chronic Chagas' disease may be made by clinical findings, supported by antibody titers if available. If there is a known history of acute disease, it is preferable to have documentation of parasites on the blood smear, if available. Exclusion Criteria Incompletely cured pre-existing diseases (except chronic Chagas' disease without active GI condition) for which it can be assumed that the absorption, distribution, metabolism, elimination, and effects of the study drugs will not be normal. Acute Chagas' disease. (During the acute phase, the parasite on a blood smear may be seen under a microscope. Different antibodies are present, depending on the course of the disease). Known hypersensitivity to the study drug (active substance or excipients of the preparations) Unstable or uncontrolled medical condition such as hypertension or diabetes, decompensated heart failure, GI conditions that would interfere with the absorption of the study drug (e.g. GI ulceration, peptic ulceration, GI bleeding, gastroesophageal reflux, or other GI disease affecting gastroesophageal junction), conditions that could potentially have an impact on drug metabolism or elimination (renal, hepatic such as known hepatic or biliary abnormalities), or any clinically relevant active infections in the opinion of the investigator within 4 weeks before the screening visit, e.g. clinically relevant history or presence of significant respiratory (e.g. interstitial lung disease), hematological, lymphatic, neurological, cardiovascular, psychiatric, musculoskeletal, genitourinary, immunological, metabolic (e.g. diabetes), and dermatological or connective tissue disease. Use of systemic or topical medicines or substances which oppose the study objectives (including clinical treatment with nifurtimox and benznidazole) or which might influence them within 4 weeks before the first study drug administration, e.g. an investigational drug, any drug altering GI motility and/or gastric pH (e.g. antacids, anticholinergic, para-sympatholytics), any drug known to induce liver enzymes (e.g. dexamethasone, barbiturates, St. John's Wort [hypericum perforatum]), any drug known to inhibit liver enzymes (e.g. ketoconazole, macrolides). Clinically relevant findings in the ECG such as a second- or third-degree atrioventricular block, prolongation of the QRS complex over 120 msec or of the QT interval over 450 msec using Bazett's formula (QTcB). (Clinically stable subjects with Chagas'-related heart disease and pacemaker in place for >1 year and evaluated by a cardiologist ≤6 months before the first dose of study drug will not be excluded.) Systolic blood pressure <100 or >140 mmHg (after resting in supine position for a minimum of 3 minutes). Diastolic blood pressure <50 or >90 mmHg (after resting in supine position for a minimum of 3 minutes). Findings that would exclude the subject in the investigator's judgment, e.g. enlarged liver, irregular heartbeat, undiagnosed acute illness, and melanoma. Positive pregnancy test. Positive results for hepatitis B virus surface antigen (HBsAg), hepatitis C virus antibodies (anti-HCV), or human immunodeficiency virus antibodies (anti-HIV 1+2). Positive urine drug screening..
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Bayer Study Director
Organizational Affiliation
Bayer
Official's Role
Study Director
Facility Information:
Facility Name
FP Clinical Pharma
City
Buenos Aires
State/Province
Ciudad Auton. De Buenos Aires
ZIP/Postal Code
C1425BAB
Country
Argentina

12. IPD Sharing Statement

Citations:
PubMed Identifier
34265407
Citation
Stass H, Just S, Weimann B, Ince I, Willmann S, Feleder E, Freitas C, Yerino G, Munster U. Clinical investigation of the biopharmaceutical characteristics of nifurtimox tablets - Implications for quality control and application. Eur J Pharm Sci. 2021 Nov 1;166:105940. doi: 10.1016/j.ejps.2021.105940. Epub 2021 Jul 12.
Results Reference
derived
Links:
URL
https://clinicaltrials.bayer.com/
Description
Click here to find results for studies related to Bayer products

Learn more about this trial

Study Will Evaluate the Relative Bioavailability, Safety, and Tolerability of Single Doses of Nifurtimox 30 mg Tablets Exhibiting Different in Vitro Dissolution Characteristics, and to Evaluate the Relative Bioavailability of Nifurtimox 30 mg and 120 mg

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