Evaluation of Whether Deferiprone Affects QT Interval in Healthy Subjects

Prolonged QTc Interval Clinical Trial

Official title:

A Double-Blind, Randomized, Crossover, Thorough QT/QTc Trial to Evaluate the Potential of Deferiprone to Prolong the QT Interval in Healthy Subjects

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01860703
• Other study ID #: LA37-1111
• Status: Completed
• Phase: Phase 4
• First received: May 6, 2013
• Last updated: November 7, 2014
• Start date: November 2012
• Est. completion date: July 2013

Study information

• Verified date: November 2014
• Source: ApoPharma
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

Randomized, single-dose, double-blind, placebo and active controlled, four-period crossover study to evaluate the effect of deferiprone on QTc prolongation after administration of a single therapeutic (33 mg/kg) and supratherapeutic(50 mg/kg) oral doses of deferiprone in healthy volunteers as compared to placebo treatment.

Description:

Post-marketing study to evaluate the effect of deferiprone and deferiprone 3-O-glucuronide on QTc prolongation in healthy volunteers after administration of a single therapeutic (33 mg/kg) and supratherapeutic (50 mg/kg) oral dose of deferiprone and moxifloxacin (Avelox®).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 50
• Est. completion date: July 2013
• Est. primary completion date: December 2012
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years to 45 Years

Eligibility

Main Inclusion Criteria:

1. Healthy adult males or females, 18 - 45 years of age (inclusive).

2. Body weight = 50 kg.

3. Body mass index (BMI) = 19 and = 32 kg/m2.

4. Medically healthy with clinically insignificant screening results (e.g., laboratory profiles, medical history, vital signs, physical examination).

5. Absolute neutrophil count (ANC) of >1.5x109/L.

6. 12-lead ECGs which have no clinically significant findings as judged by the Principal Investigator (PI) or the PI's designee at screening and check-in of each study period,including:

1. Normal sinus rhythm (heart rate between 45 and 100 bpm);

2. QTcF interval = 450 msec;

3. QRS interval = 110 msec; and

4. PR interval = 220 msec.

7. Subject must be capable of providing written informed consent, and must voluntarily consent to participate in the study.

8. Willing to answer inclusion and exclusion criteria questionnaire at check-in.

Main Exclusion Criteria:

1. History or presence of significant respiratory, cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic,neurologic, or psychiatric disease.

2. Disorders or surgery of the gastrointestinal tract which may interfere with drug absorption or may otherwise influence the PK of the investigational medicinal products (e.g. cholecystectomy, resections of the small or large intestine, febrile conditions, chronic diarrhea, chronic vomiting, endocrine disease, severe infections,acute inflammations, etc.).

3. Presence of liver impairment: aspartate aminotransferase (AST), alanine aminotransferase (ALT) above the normal reference range.

4. Presence of significant kidney impairment: serum creatinine higher than the normal reference range.

5. Allergy to band aids, adhesive dressing or medical tape.

6. Clinically significant history or presence of ECG abnormalities such as second- or third-degree atrioventricular block; evidence, or family history, of prolonged QT syndrome.

7. Sustained sitting systolic blood pressure of <90 mmHg or >140 mmHg, or diastolic blood pressure of >95 mmHg at screening or check-in of Period 1.

8. History or presence of hypersensitivity or idiosyncratic reaction to deferiprone, moxifloxacin, iron chelators, or quinolone antibiotics.

9. History or presence of:

• agranulocytosis;

• asthma;

• chronic bronchitis;

• diabetes;

• migraine;

• hypertension;

• hypotension;

• hypokalemia;

• seizures or epilepsy;

• anaemia.

10. History or presence of alcoholism or drug abuse within the past 2 years.

11. Used tobacco/nicotine-containing product for at least 3 months prior to the first dose of study.

12. Used Depo-Provera® or levonorgestrel implant within 90 days prior to the first dose and throughout the study.

13. Participation in another clinical trial within 28 days prior to the first dose of the study.

14. Had a clinically significant illness during the 4 weeks prior to check-in on Day -1 of Period 1.

Study Design

Allocation: Randomized, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Prolonged QTc Interval

Intervention

Drug:
• Deferiprone
Ferriprox 500 mg tablets
• deferiprone matching placebo tablets
deferiprone matching placebo tablets
• moxifloxacin
Active control
• placebo
moxifloxacin-matching placebo

Locations

Country	Name	City	State
United States	Celerion	Tempe	Arizona

Sponsors (1)

Lead Sponsor	Collaborator
ApoPharma

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum Difference in Change From Baseline in ddQTcF Following a Single Dose of 33 mg/kg Deferiprone	Change from baseline in QTcF interval was measured by looking at the post-dose difference in change from baseline in Fridericia's QT corrected heart rate (dQTcF) between treatment and placebo (ddQTcF) at each time interval.; ECG recordings were obtained within a 5-minute time window at Hours -0.75, -0.5, and -0.25 (prior to dosing) and Hours 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, and 24 post-dose.	24-hour interval	No
Primary	Maximum Difference in Change From Baseline in ddQTcF Following a Single Dose of 50 mg/kg Deferiprone	Change from baseline in QTcF interval was measured by looking at the post-dose difference in change from baseline in Fridericia's QT corrected heart rate (dQTcF) between treatment and placebo (ddQTcF) at each time interval.; ECG recordings were obtained within a 5-minute time window at Hours -0.75, -0.5, and -0.25 (prior to dosing) and Hours 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, and 24 post-dose.	24-hour interval	No
Primary	Maximum Postdose QT/QTc Interval	The maximum post-dose QT/QTc interval for deferiprone and placebo.; ECG recordings were obtained within a 5-minute time window at Hours -0.75, -0.5, and -0.25 (prior to dosing) and Hours 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, and 24 post-dose.	24-hour interval	No
Primary	Maximum Change From Baseline (dQT/dQTc)	Maximum Change From Baseline (dQT/dQTc) for deferiprone and placebo.; ECG recordings were obtained within a 5-minute time window at Hours -0.75, -0.5, and -0.25 (prior to dosing) and Hours 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, and 24 post-dose.	24-hour interval	No
Secondary	Number of Participants With Adverse Events	Number of participants with adverse events following therapeutic and supratherapeutic doses of deferiprone	From administration of the first dose until 7 days +/- 1 day following the final dose	Yes
Secondary	Cmax of Deferiprone and Deferiprone 3-O Glucuronide	To evaluate the Cmax of deferiprone and deferiprone 3-O-glucuronide following administration of single doses of 33 and 50 mg/kg deferiprone in healthy volunteers.; Serial blood samples were collected prior to dosing and within 5 minutes following completion of each scheduled post-dose ECG at Hours 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, and 24 post-dose.	24-hour interval	No
Secondary	Tmax of Deferiprone and Deferiprone 3-O-glucuronide	To evaluate the Tmax of deferiprone and deferiprone 3-O-glucuronide following administration of single doses of 33 and 50 mg/kg deferiprone in healthy volunteers.; Serial blood samples were collected prior to dosing and within 5 minutes following completion of each scheduled post-dose ECG at Hours 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, and 24 post-dose.	24-hour interval	No
Secondary	AUC0-infinity for Serum Deferiprone and Deferiprone 3-O-glucuronide	AUC0-infinity was assessed over a 24-hour interval for analyses of deferiprone and its 3-O-glucuronide metabolite in healthy volunteers.; Serial blood samples were collected prior to dosing and within 5 minutes following completion of each scheduled post-dose ECG at Hours 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, and 24 post-dose.	24-hour interval	No
Secondary	T1/2 for Serum Deferiprone and Deferiprone 3-O-glucuronide	T1/2 was assessed over a 24-hour interval for analyses of deferiprone and its 3-O-glucuronide metabolite in healthy volunteers.; Serial blood samples were collected prior to dosing and within 5 minutes following completion of each scheduled post-dose ECG at Hours 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, and 24 post-dose.	24-hour interval	No
Secondary	Maximum Difference in Change From Baseline in ddQTcF Following a Single Dose of Moxifloxacin	Change from baseline in QTcF interval was measured by looking at the post-dose difference in change from baseline in Fridericia's QT corrected heart rate (dQTcF) between treatment and placebo (ddQTcF) at each time interval.; ECG recordings were obtained within a 5-minute time window at Hours -0.75, -0.5, and -0.25 (prior to dosing) and Hours 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, and 24 post-dose.	24-hour interval	No