Evaluation of Whether Deferiprone Affects QT Interval in Healthy Subjects

Study Overview
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Brief Summary
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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.

Detailed Description
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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®).

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

Conditions
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Prolonged QTc Interval

Intervention / Treatment
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* Drug: Deferiprone
* Drug: deferiprone matching placebo tablets
* Drug: moxifloxacin
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Main Inclusion Criteria: Healthy adult males or females, 18 - 45 years of age (inclusive). Body weight ≥ 50 kg. Body mass index (BMI) ≥ 19 and ≤ 32 kg/m2. Medically healthy with clinically insignificant screening results (e.g., laboratory profiles, medical history, vital signs, physical examination). Absolute neutrophil count (ANC) of >1.5x109/L. 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: Normal sinus rhythm (heart rate between 45 and 100 bpm); QTcF interval ≤ 450 msec; QRS interval ≤ 110 msec; and PR interval ≤ 220 msec. Subject must be capable of providing written informed consent, and must voluntarily consent to participate in the study. Willing to answer inclusion and exclusion criteria questionnaire at check-in. Main Exclusion Criteria: History or presence of significant respiratory, cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic,neurologic, or psychiatric disease. 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.). Presence of liver impairment: aspartate aminotransferase (AST), alanine aminotransferase (ALT) above the normal reference range. Presence of significant kidney impairment: serum creatinine higher than the normal reference range. Allergy to band aids, adhesive dressing or medical tape. Clinically significant history or presence of ECG abnormalities such as second- or third-degree atrioventricular block; evidence, or family history, of prolonged QT syndrome. 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. History or presence of hypersensitivity or idiosyncratic reaction to deferiprone, moxifloxacin, iron chelators, or quinolone antibiotics. History or presence of: agranulocytosis; asthma; chronic bronchitis; diabetes; migraine; hypertension; hypotension; hypokalemia; seizures or epilepsy; anaemia. History or presence of alcoholism or drug abuse within the past 2 years. Used tobacco/nicotine-containing product for at least 3 months prior to the first dose of study. Used Depo-Provera® or levonorgestrel implant within 90 days prior to the first dose and throughout the study. Participation in another clinical trial within 28 days prior to the first dose of the study. Had a clinically significant illness during the 4 weeks prior to check-in on Day -1 of Period 1.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A - Maximum Therapeutic Dose<br>Single dose of 33 mg/kg rounded to the nearest 250 mg of deferiprone tablets | Drug: Deferiprone<br>* Ferriprox 500 mg tablets<br>* Other names: L1;|
| Experimental: Treatment Arm B - Supratherapeutic Dose<br>Single dose of 50 mg/kg rounded to the nearest 250 mg of deferiprone tablets | Drug: Deferiprone<br>* Ferriprox 500 mg tablets<br>* Other names: L1;|
| Experimental: Arm C - Placebo Control<br>Single dose of matching deferiprone and moxifloxacin placebo tablets. | Drug: deferiprone matching placebo tablets<br>* deferiprone matching placebo tablets<br>* Other names: Placebo;Drug: placebo<br>* moxifloxacin-matching placebo<br>|
| Experimental: Arm D - Positive Control<br>Single dose of one 400 mg moxifloxacin tablet. | Drug: moxifloxacin<br>* Active control<br>* Other names: Avelox;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ferriprox®, LI, DFP, Deferiprone, Healthy Volunteers