Evaluation of Whether Deferiprone Affects QT Interval in Healthy Subjects

• Sponsor: ApoPharma (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01860703
• Collaborator: (none)
• Enrollment: 50
• Location: 1
• Arms: 4
• Duration (Months): 8
• Patients Per Site Per Month: 6.3

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Prolonged QTc Interval	Drug: Deferiprone; Drug: deferiprone matching placebo tablets; Drug: moxifloxacin; Drug: placebo	Phase 4

Detailed 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®).

Study Design

• Study Type: Interventional
• Actual Enrollment: 50 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• 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
• Study Start Date: Nov 1, 2012
• Actual Primary Completion Date: Dec 1, 2012
• Actual Study Completion Date: Jul 1, 2013

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Maximum Difference in Change From Baseline in ddQTcF Following a Single Dose of 33 mg/kg Deferiprone [24-hour interval]

   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.

2. Maximum Difference in Change From Baseline in ddQTcF Following a Single Dose of 50 mg/kg Deferiprone [24-hour interval]

   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.

3. Maximum Postdose QT/QTc Interval [24-hour 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.

4. Maximum Change From Baseline (dQT/dQTc) [24-hour interval]

   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.

Secondary Outcome Measures

1. Number of Participants With Adverse Events [From administration of the first dose until 7 days +/- 1 day following the final dose]

   Number of participants with adverse events following therapeutic and supratherapeutic doses of deferiprone

2. Cmax of Deferiprone and Deferiprone 3-O Glucuronide [24-hour interval]

   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.

3. Tmax of Deferiprone and Deferiprone 3-O-glucuronide [24-hour interval]

   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.

4. AUC0-infinity for Serum Deferiprone and Deferiprone 3-O-glucuronide [24-hour interval]

   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.

5. T1/2 for Serum Deferiprone and Deferiprone 3-O-glucuronide [24-hour interval]

   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.

6. Maximum Difference in Change From Baseline in ddQTcF Following a Single Dose of Moxifloxacin [24-hour interval]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 45 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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:

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

8. QTcF interval ≤ 450 msec;

9. QRS interval ≤ 110 msec; and

10. PR interval ≤ 220 msec.

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

12. 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.

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

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

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

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

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Celerion	Tempe	Arizona	United States	85283

Sponsors and Collaborators

• ApoPharma

Investigators

• Study Chair: Fernando Tricta, MD, ApoPharma
• Study Director: Caroline Fradette, PhD, ApoPharma

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: ApoPharma
• ClinicalTrials.gov Identifier: NCT01860703
• Other Study ID Numbers: LA37-1111
• First Posted: May 23, 2013
• Last Update Posted: Nov 12, 2014
• Last Verified: Nov 1, 2014

• Keywords provided by ApoPharma: Ferriprox®; LI; DFP; Deferiprone; Healthy Volunteers
• Additional relevant MeSH terms: Moxifloxacin; Deferiprone

Study Results

Participant Flow

Recruitment Details	First subject enrolled: 17 November 2012 Last subject completed: 19 December 2012 The study was carried out at Celerion, a research facility used for conducting clinical trials.

Arm/Group Title	ABCD	BDAC	CADB	DCBA
Arm/Group Description	All subjects received the same 4 treatments, separated by at least 7 days of washout, but were randomized to receive them in different orders. Subjects in this arm received them in the following order: Treatment A = single oral dose of 33 mg/kg deferiprone Treatment B = single oral dose of 50 mg/kg deferiprone Treatment C = single oral dose of placebo Treatment D = single oral dose of moxifloxacin	All subjects received the same 4 treatments, separated by at least 7 days of washout, but were randomized to receive them in different orders. Subjects in this arm received them in the following order: Treatment B = single oral dose of 50 mg/kg deferiprone Treatment D = single oral dose of moxifloxacin Treatment A = single oral dose of 33 mg/kg deferiprone Treatment C = single oral dose of placebo	All subjects received the same 4 treatments, separated by at least 7 days of washout, but were randomized to receive them in different orders. Subjects in this arm received them in the following order: Treatment C = single oral dose of placebo Treatment A = single oral dose of 33 mg/kg deferiprone Treatment D = single oral dose of moxifloxacin Treatment B = single oral dose of 50 mg/kg deferiprone	All subjects received the same 4 treatments, separated by at least 7 days of washout, but were randomized to receive them in different orders. Subjects in this arm received them in the following order: Treatment D = single oral dose of moxifloxacin Treatment C = single oral dose of placebo Treatment B = single oral dose of 50 mg/kg deferiprone Treatment A = single oral dose of 33 mg/kg deferiprone
Period Title: Overall Study
STARTED	13	13	12	12
COMPLETED	11	8	11	10
NOT COMPLETED	2	5	1	2

Baseline Characteristics

Arm/Group Title	All Subjects
Arm/Group Description	Subjects in this cross-over study all received one dose of each the following: A) a maximum therapeutic dose of 33 mg deferiprone, B) a supratherapeutic dose of 50 mg/kg deferiprone, C) placebo, and D) moxifloxacin (active control). They were randomized to receive these products in different orders: ABCD, BDAC, CADB, or DCBA. Treatments were separated by a 7-day washout period.
Overall Participants	50
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	50 100%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	29 58%
Male	21 42%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	46 92%
Not Hispanic or Latino	4 8%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 2%
White	49 98%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	50 100%

Outcome Measures

1. Primary Outcome

Title	Maximum Difference in Change From Baseline in ddQTcF Following a Single Dose of 33 mg/kg Deferiprone
Description	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.
Time Frame	24-hour interval

Outcome Measure Data

Analysis Population Description

Cardiodynamic Analysis Set : all randomized subjects who received at least 1 dose of study medication and who had valid Day 1 QT/QTc interval measurements (predose and at least one postdose measurement).

Arm/Group Title	33 mg/kg Deferiprone	Placebo Control
Arm/Group Description	A single dose of deferiprone 500 mg tablets at a dosage of 33 mg/kg (the maximum therapeutic level), rounded to the nearest 250 mg. Subjects additionally received deferiprone-matching placebo tablets to provide the same total number of tablets as for a 50 mg/kg dose, plus 1 moxifloxacin-matching placebo tablet. Tablets were administered orally with approximately 240 mL of water.	A single dose of deferiprone -matching placebo tablets to provide the same total number of tablets as for a 50 mg/kg dose. Subjects additionally received 1 moxifloxacin-matching placebo tablet. Tablets were administered orally with approximately 240 mL of water.
Measure Participants	46	45
Least Squares Mean (Standard Deviation) [milliseconds]	1.4 (4.92)	-1.6 (4.72)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	33 mg/kg Deferiprone, Placebo Control
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.01
	Confidence Interval	(2-Sided) 90%; 1.02 to 5.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Number of Participants With Adverse Events
Description	Number of participants with adverse events following therapeutic and supratherapeutic doses of deferiprone
Time Frame	From administration of the first dose until 7 days +/- 1 day following the final dose

Outcome Measure Data

Analysis Population Description

The Safety Analysis Set consisted of all subjects who received at least 1 dose of study medication and had at least 1 safety assessment.

Arm/Group Title	Arm A - Maximum Therapeutic Dose	Treatment Arm B - Supratherapeutic Dose	Arm C - Placebo Control	Arm D - Positive Control
Arm/Group Description	A single dose of deferiprone 500 mg tablets at a dosage of 33 mg/kg (the maximum therapeutic level), rounded to the nearest 250 mg. Subjects additionally received deferiprone-matching placebo tablets to provide the same total number of tablets as for a 50 mg/kg dose, plus 1 moxifloxacin-matching placebo tablet. Tablets were administered orally with approximately 240 mL of water.	A single dose of deferiprone 500 mg tablets at a dosage of 50 mg/kg (a supra-therapeutic level), rounded to the nearest 250 mg. Subjects additionally received 1 moxifloxacin-matching placebo tablet. Tablets were administered orally with approximately 240 mL of water.	A single dose of deferiprone-matching placebo tablets to provide the same total number of tablets as for a 50 mg/kg dose. Subjects additionally received 1 moxifloxacin-matching placebo tablet. Tablets were administered orally with approximately 240 mL of water.	One 400 mg moxifloxacin tablet. Subjects additionally received a single dose of deferiprone-matching placebo tablets to provide the same total number of tablets as for a 50 mg/kg dose. Tablets were administered orally with approximately 240 mL of water.
Measure Participants	46	48	45	46
Number [participants]	12 24%	35 NaN	10 NaN	5 NaN

3. Secondary Outcome

Title	Cmax of Deferiprone and Deferiprone 3-O Glucuronide
Description	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.
Time Frame	24-hour interval

Outcome Measure Data

Analysis Population Description

The PK population consisted of all subjects who had taken study medication and had at least 1 PK sample collected.

Arm/Group Title	Arm A - Maximum Therapeutic Dose	Treatment Arm B - Supratherapeutic Dose
Arm/Group Description	A single dose of deferiprone 500 mg tablets at a dosage of 33 mg/kg (the maximum therapeutic level), rounded to the nearest 250 mg. Subjects additionally received deferiprone-matching placebo tablets to provide the same total number of tablets as for a 50 mg/kg dose, plus 1 moxifloxacin-matching placebo tablet. Tablets were administered orally with approximately 240 mL of water.	A single dose of deferiprone 500 mg tablets at a dosage of 50 mg/kg (a supra-therapeutic level), rounded to the nearest 250 mg. Subjects additionally received 1 moxifloxacin-matching placebo tablet. Tablets were administered orally with approximately 240 mL of water.
Measure Participants	46	48
Cmax of serum deferiprone	34.1 (8.9)	54.4 (16.4)
Cmax of serum deferiprone 3-O-glucuronide	35.2 (8.5)	51.4 (13.4)

4. Secondary Outcome

Title	Tmax of Deferiprone and Deferiprone 3-O-glucuronide
Description	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.
Time Frame	24-hour interval

Outcome Measure Data

Analysis Population Description

The PK population consisted of all subjects who had taken study medication and had at least 1 PK sample collected.

Arm/Group Title	Arm A - Maximum Therapeutic Dose	Treatment Arm B - Supratherapeutic Dose
Arm/Group Description	A single dose of deferiprone 500 mg tablets at a dosage of 33 mg/kg (the maximum therapeutic level), rounded to the nearest 250 mg. Subjects additionally received deferiprone-matching placebo tablets to provide the same total number of tablets as for a 50 mg/kg dose, plus 1 moxifloxacin-matching placebo tablet. Tablets were administered orally with approximately 240 mL of water.	A single dose of deferiprone 500 mg tablets at a dosage of 50 mg/kg (a supra-therapeutic level), rounded to the nearest 250 mg. Subjects additionally received 1 moxifloxacin-matching placebo tablet. Tablets were administered orally with approximately 240 mL of water.
Measure Participants	46	48
Tmax of serum deferiprone	0.8185 (0.6)	0.8175 (0.9)
Tmax of serum deferiprone -O-glucuronide	3.066 (0.7)	3.071 (0.7)

5. Secondary Outcome

Title	AUC0-infinity for Serum Deferiprone and Deferiprone 3-O-glucuronide
Description	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.
Time Frame	24-hour interval

Outcome Measure Data

Analysis Population Description

The PK population consisted of all subjects who had taken study medication and had at least 1 PK sample collected.

Arm/Group Title	Arm A - Maximum Therapeutic Dose	Treatment Arm B - Supratherapeutic Dose
Arm/Group Description	A single dose of deferiprone 500 mg tablets at a dosage of 33 mg/kg (the maximum therapeutic level), rounded to the nearest 250 mg. Subjects additionally received deferiprone-matching placebo tablets to provide the same total number of tablets as for a 50 mg/kg dose, plus 1 moxifloxacin-matching placebo tablet. Tablets were administered orally with approximately 240 mL of water.	A single dose of deferiprone 500 mg tablets at a dosage of 50 mg/kg (a supra-therapeutic level), rounded to the nearest 250 mg. Subjects additionally received 1 moxifloxacin-matching placebo tablet. Tablets were administered orally with approximately 240 mL of water.
Measure Participants	46	48
AUC0-infinity for serum deferiprone	95.4 (18.03)	152.1 (22.2)
AUC0-infinity for serum deferiprone -O-glucuronide	205.5 (42.8)	331.2 (74.7)

6. Secondary Outcome

Title	T1/2 for Serum Deferiprone and Deferiprone 3-O-glucuronide
Description	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.
Time Frame	24-hour interval

Outcome Measure Data

Analysis Population Description

The PK population consisted of all subjects who had taken study medication and had at least 1 PK sample collected.

Arm/Group Title	Arm A - Maximum Therapeutic Dose	Treatment Arm B - Supratherapeutic Dose
Arm/Group Description	A single dose of deferiprone 500 mg tablets at a dosage of 33 mg/kg (the maximum therapeutic level), rounded to the nearest 250 mg. Subjects additionally received deferiprone-matching placebo tablets to provide the same total number of tablets as for a 50 mg/kg dose, plus 1 moxifloxacin-matching placebo tablet. Tablets were administered orally with approximately 240 mL of water.	A single dose of deferiprone 500 mg tablets at a dosage of 50 mg/kg (a supra-therapeutic level), rounded to the nearest 250 mg. Subjects additionally received 1 moxifloxacin-matching placebo tablet. Tablets were administered orally with approximately 240 mL of water.
Measure Participants	46	48
T1/2 for serum deferiprone	1.8 (0.3)	1.8 (0.3)
T1/2 for serum deferiprone 3-O-glucuronide	2.5 (0.5)	2.6 (0.2)

7. Primary Outcome

Title	Maximum Difference in Change From Baseline in ddQTcF Following a Single Dose of 50 mg/kg Deferiprone
Description	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.
Time Frame	24-hour interval

Outcome Measure Data

Analysis Population Description

Cardiodynamic Analysis Set : all randomized subjects who received at least 1 dose of study medication and who had valid Day 1 QT/QTc interval measurements (predose and at least one postdose measurement).

Arm/Group Title	50 mg/kg Deferiprone	Placebo Control
Arm/Group Description	A single dose of deferiprone 500 mg tablets at a dosage of 50 mg/kg (a supra-therapeutic level), rounded to the nearest 250 mg. Subjects additionally received 1 moxifloxacin-matching placebo tablet. Tablets were administered orally with approximately 240 mL of water.	A single dose of deferiprone -matching placebo tablets to provide the same total number of tablets as for a 50 mg/kg dose. Subjects additionally received 1 moxifloxacin-matching placebo tablet. Tablets were administered orally with approximately 240 mL of water.
Measure Participants	48	45
Least Squares Mean (Standard Deviation) [milliseconds]	3.5 (5.28)	-1.7 (6.36)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	33 mg/kg Deferiprone, Placebo Control
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	5.23
	Confidence Interval	(2-Sided) 90%; 3.26 to 7.19
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Primary Outcome

Title	Maximum Postdose QT/QTc Interval
Description	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.
Time Frame	24-hour interval

Outcome Measure Data

Analysis Population Description

The Cardiodynamic Analysis Set consisted of all randomized subjects who received at least 1 dose of study medication and who had valid Day 1 QT/QTc interval measurements (predose and at least one postdose measurement).

Arm/Group Title	Arm A - Maximum Therapeutic Dose	Arm B - Supratherapeutic Dose	Arm C - Placebo Control	Arm D - Positive Control
Arm/Group Description	A single dose of deferiprone 500 mg tablets at a dosage of 33 mg/kg (the maximum therapeutic level), rounded to the nearest 250 mg. Subjects additionally received deferiprone-matching placebo tablets to provide the same total number of tablets as for a 50 mg/kg dose, plus 1 moxifloxacin-matching placebo tablet. Tablets were administered orally with approximately 240 mL of water.	A single dose of deferiprone 500 mg tablets at a dosage of 50 mg/kg (a supra-therapeutic level), rounded to the nearest 250 mg. Subjects additionally received 1 moxifloxacin-matching placebo tablet. Tablets were administered orally with approximately 240 mL of water.	A single dose of deferiprone -matching placebo tablets to provide the same total number of tablets as for a 50 mg/kg dose. Subjects additionally received 1 moxifloxacin-matching placebo tablet. Tablets were administered orally with approximately 240 mL of water.	One 400 mg moxifloxacin tablet. Subjects additionally received a single dose of deferiprone-matching placebo tablets to provide the same total number of tablets as for a 50 mg/kg dose. Tablets were administered orally with approximately 240 mL of water.
Measure Participants	46	48	45	46
QTcF ≤ 450 msec	100 200%	96 NaN	98 NaN	89 NaN
QTcF > 450 to ≤ 480 msec	0 0%	4 NaN	2 NaN	11 NaN
QTcF > 480 to ≤ 500 msec	0 0%	0 NaN	0 NaN	0 NaN
QTcF > 500 msec	0 0%	0 NaN	0 NaN	0 NaN

9. Primary Outcome

Title	Maximum Change From Baseline (dQT/dQTc)
Description	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.
Time Frame	24-hour interval

Outcome Measure Data

Analysis Population Description

The Cardiodynamic Analysis Set consisted of all randomized subjects who received at least 1 dose of study medication and who had valid Day 1 QT/QTc interval measurements (predose and at least one postdose measurement).

Arm/Group Title	Arm A - Maximum Therapeutic Dose	Arm B - Supratherapeutic Dose	Arm C - Placebo Control	Arm D - Positive Control
Arm/Group Description	A single dose of deferiprone 500 mg tablets at a dosage of 33 mg/kg (the maximum therapeutic level), rounded to the nearest 250 mg. Subjects additionally received deferiprone-matching placebo tablets to provide the same total number of tablets as for a 50 mg/kg dose, plus 1 moxifloxacin-matching placebo tablet. Tablets were administered orally with approximately 240 mL of water.	A single dose of deferiprone 500 mg tablets at a dosage of 50 mg/kg (a supra-therapeutic level), rounded to the nearest 250 mg. Subjects additionally received 1 moxifloxacin-matching placebo tablet. Tablets were administered orally with approximately 240 mL of water.	A single dose of deferiprone-matching placebo tablets to provide the same total number of tablets as for a 50 mg/kg dose. Subjects additionally received 1 moxifloxacin-matching placebo tablet. Tablets were administered orally with approximately 240 mL of water.	One 400 mg moxifloxacin tablet. Subjects additionally received a single dose of deferiprone-matching placebo tablets to provide the same total number of tablets as for a 50 mg/kg dose. Tablets were administered orally with approximately 240 mL of water.
Measure Participants	46	48	45	46
QTcF ≤ 30 msec	100 200%	100 NaN	100 NaN	96 NaN
QTcF >30 but ≤ 60 msec	0 0%	0 NaN	0 NaN	4 NaN
QTcF >60 msec	0 0%	0 NaN	0 NaN	0 NaN

10. Secondary Outcome

Title	Maximum Difference in Change From Baseline in ddQTcF Following a Single Dose of Moxifloxacin
Description	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.
Time Frame	24-hour interval

Outcome Measure Data

Analysis Population Description

Cardiodynamic Analysis Set : all randomized subjects who received at least 1 dose of study medication and who had valid Day 1 QT/QTc interval measurements (predose and at least one postdose measurement).

Arm/Group Title	Positive Control	Placebo Control
Arm/Group Description	A single 400 mg tablet of moxifloxacin. The tablet was administered orally with approximately 240 mL of water.	A single dose of deferiprone -matching placebo tablets to provide the same total number of tablets as for a 50 mg/kg dose. Subjects additionally received 1 moxifloxacin-matching placebo tablet. Tablets were administered orally with approximately 240 mL of water.
Measure Participants	46	45
Least Squares Mean (Standard Deviation) [milliseconds]	14.7 (6.38)	1.2 (6.46)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	33 mg/kg Deferiprone, Placebo Control
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	13.42
	Confidence Interval	(2-Sided) 90%; 11.10 to 15.75
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Adverse events were collected from the time of the first dose until 7 days (± 1 day) following the last study event of Period 4 or following early withdrawal.
Arm/Group Title	Treatment Arm A - Maximum Therapeutic Dose		Treatment Arm B - Supratherapeutic Dose		Treatment Arm C - Placebo Control		Treatment Arm D - Positive Control
Arm/Group Description	Single dose of 33 mg/kg rounded to the nearest 250 mg of deferiprone tablets, deferiprone matching placebo tablets and one moxifloxacin matching placebo tablet. Deferiprone deferiprone matching placebo tablets moxifloxacin matching placebo tablet		Single dose of 50 mg/kg rounded to the nearest 250 mg of deferiprone tablets, and one moxifloxacin matching placebo tablet. Deferiprone moxifloxacin matching placebo tablet		Single dose of deferiprone matching placebo tablets and one moxifloxacin matching placebo tablet. deferiprone matching placebo tablets moxifloxacin matching placebo tablet		Single dose of deferiprone matching placebo tablets and one 400 mg moxifloxacin tablet. Deferiprone moxifloxacin
All Cause Mortality
	Treatment Arm A - Maximum Therapeutic Dose		Treatment Arm B - Supratherapeutic Dose		Treatment Arm C - Placebo Control		Treatment Arm D - Positive Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Treatment Arm A - Maximum Therapeutic Dose		Treatment Arm B - Supratherapeutic Dose		Treatment Arm C - Placebo Control		Treatment Arm D - Positive Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/46 (0%)		0/48 (0%)		0/45 (0%)		0/46 (0%)
Other (Not Including Serious) Adverse Events
	Treatment Arm A - Maximum Therapeutic Dose		Treatment Arm B - Supratherapeutic Dose		Treatment Arm C - Placebo Control		Treatment Arm D - Positive Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/46 (26.1%)		35/48 (72.9%)		10/45 (22.2%)		5/46 (10.9%)
Cardiac disorders
Palpitations	1/46 (2.2%)	2	2/48 (4.2%)	2	2/45 (4.4%)	2	0/46 (0%)	0
Sinus arrest	0/46 (0%)	0	1/48 (2.1%)	1	0/45 (0%)	0	0/46 (0%)	0
Gastrointestinal disorders
Abdominal pain lower	1/46 (2.2%)	1	1/48 (2.1%)	1	0/45 (0%)	0	0/46 (0%)	0
Dyspepsia	0/46 (0%)	0	1/48 (2.1%)	1	0/45 (0%)	0	0/46 (0%)	0
Eructation	0/46 (0%)	0	1/48 (2.1%)	1	0/45 (0%)	0	0/46 (0%)	0
Nausea	7/46 (15.2%)	8	19/48 (39.6%)	20	2/45 (4.4%)	2	1/46 (2.2%)	1
Vomiting	2/46 (4.3%)	2	14/48 (29.2%)	15	0/45 (0%)	0	1/46 (2.2%)	1
General disorders
Asthenia	1/46 (2.2%)	1	0/48 (0%)	0	0/45 (0%)	0	0/46 (0%)	0
Chest discomfort	0/46 (0%)	0	0/48 (0%)	0	1/45 (2.2%)	1	0/46 (0%)	0
Chills	0/46 (0%)	0	2/48 (4.2%)	2	0/45 (0%)	0	0/46 (0%)	0
Fatigue	0/46 (0%)	0	1/48 (2.1%)	1	0/45 (0%)	0	0/46 (0%)	0
Feeling hot	0/46 (0%)	0	4/48 (8.3%)	4	0/45 (0%)	0	0/46 (0%)	0
Irritability	1/46 (2.2%)	1	0/48 (0%)	0	0/45 (0%)	0	0/46 (0%)	0
Sensation of foreign body	1/46 (2.2%)	1	0/48 (0%)	0	0/45 (0%)	0	0/46 (0%)	0
Infections and infestations
Upper respiratory tract infection	0/46 (0%)	0	0/48 (0%)	0	1/45 (2.2%)	1	0/46 (0%)	0
Urinary tract infection	0/46 (0%)	0	1/48 (2.1%)	1	0/45 (0%)	0	0/46 (0%)	0
Injury, poisoning and procedural complications
Procedural dizziness	0/46 (0%)	0	1/48 (2.1%)	1	0/45 (0%)	0	0/46 (0%)	0
Investigations
Electrocardiogram QRS complex prolonged	0/46 (0%)	0	0/48 (0%)	0	1/45 (2.2%)	1	0/46 (0%)	0
Electrocardiogram QT prolonged	1/46 (2.2%)	1	0/48 (0%)	0	0/45 (0%)	0	0/46 (0%)	0
Haemoglobin decreased	0/46 (0%)	0	1/48 (2.1%)	1	0/45 (0%)	0	0/46 (0%)	0
Red blood cells urine positive	0/46 (0%)	0	1/48 (2.1%)	1	0/45 (0%)	0	0/46 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	0/46 (0%)	0	1/48 (2.1%)	2	0/45 (0%)	0	0/46 (0%)	0
Musculoskeletal chest pain	0/46 (0%)	0	0/48 (0%)	0	1/45 (2.2%)	1	0/46 (0%)	0
Musculoskeletal discomfort	0/46 (0%)	0	1/48 (2.1%)	1	0/45 (0%)	0	0/46 (0%)	0
Myalgia	0/46 (0%)	0	1/48 (2.1%)	1	0/45 (0%)	0	0/46 (0%)	0
Neck pain	1/46 (2.2%)	1	0/48 (0%)	0	0/45 (0%)	0	0/46 (0%)	0
Nervous system disorders
Dizziness	3/46 (6.5%)	3	6/48 (12.5%)	6	1/45 (2.2%)	1	0/46 (0%)	0
Dizziness postural	0/46 (0%)	0	0/48 (0%)	0	0/45 (0%)	0	1/46 (2.2%)	1
Formication	0/46 (0%)	0	1/48 (2.1%)	1	0/45 (0%)	0	0/46 (0%)	0
Headache	8/46 (17.4%)	10	32/48 (66.7%)	34	7/45 (15.6%)	7	3/46 (6.5%)	3
Paraesthesia	0/46 (0%)	0	1/48 (2.1%)	1	0/45 (0%)	0	0/46 (0%)	0
Presyncope	1/46 (2.2%)	1	0/48 (0%)	0	0/45 (0%)	0	0/46 (0%)	0
Somnolence	1/46 (2.2%)	1	0/48 (0%)	0	0/45 (0%)	0	0/46 (0%)	0
Syncope	0/46 (0%)	0	1/48 (2.1%)	1	0/45 (0%)	0	0/46 (0%)	0
Psychiatric disorders
Abnormal dreams	0/46 (0%)	0	1/48 (2.1%)	1	0/45 (0%)	0	0/46 (0%)	0
Anxiety	2/46 (4.3%)	2	0/48 (0%)	0	0/45 (0%)	0	0/46 (0%)	0
Renal and urinary disorders
Chromaturia	1/46 (2.2%)	1	2/48 (4.2%)	2	0/45 (0%)	0	0/46 (0%)	0
Reproductive system and breast disorders
Metrorrhagia	0/46 (0%)	0	0/48 (0%)	0	1/45 (2.2%)	1	0/46 (0%)	0
Pelvic pain	0/46 (0%)	0	1/48 (2.1%)	1	0/45 (0%)	0	0/46 (0%)	0
Vaginal discharge	1/46 (2.2%)	1	0/48 (0%)	0	0/45 (0%)	0	0/46 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/46 (2.2%)	1	0/48 (0%)	0	0/45 (0%)	0	0/46 (0%)	0
Epistaxis	0/46 (0%)	0	0/48 (0%)	0	0/45 (0%)	0	1/46 (2.2%)	1
Nasal ulcer	1/46 (2.2%)	1	0/48 (0%)	0	0/45 (0%)	0	0/46 (0%)	0
Oropharyngeal pain	0/46 (0%)	0	1/48 (2.1%)	1	0/45 (0%)	0	0/46 (0%)	0
Skin and subcutaneous tissue disorders
Dermatitis contact	1/46 (2.2%)	1	0/48 (0%)	0	0/45 (0%)	0	0/46 (0%)	0
Hyperhidrosis	0/46 (0%)	0	1/48 (2.1%)	1	0/45 (0%)	0	0/46 (0%)	0
Vascular disorders
Pallor	0/46 (0%)	0	1/48 (2.1%)	1	0/45 (0%)	0	0/46 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

All unpublished information given to the CRO by ApoPharma shall not be published or disclosed to a third party without the prior written consent of ApoPharma. The data generated by this study are considered confidential information and the property of ApoPharma. This confidential information may be published only in collaboration with participating personnel from ApoPharma or upon ApoPharma written consent to publish the article.