TWICE: Safety and Acceptability of Deferiprone Delayed Release Tablets in Patients With Systemic Iron Overload

• Sponsor: ApoPharma (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03802916
• Collaborator: (none)
• Enrollment: 30
• Locations: 5
• Arms: 2
• Actual Duration (Months): 9.5
• Patients Per Site: 6
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

Safety, tolerability, and acceptability of twice-daily dosing with deferiprone delayed-release (DR) tablets in patients with systemic iron overload.

Condition or Disease	Intervention/Treatment	Phase
Iron Overload Due to Repeated Red Blood Cell Transfusions	Drug: Deferiprone DR tablets 1000 mg (Low dosage); Drug: Deferiprone DR tablets 1000 mg (High dosage)	Phase 2

Detailed Description

This study is looking at the safety, tolerability, and acceptability of twice-daily dosing with deferiprone delayed-release (DR) tablets in patients with systemic iron overload who are currently taking deferiprone immediate-release tablets (Ferriprox) three times a day. Ferriprox doses range from 75 milligrams per kilogram of body weight (mg/kg) per day to 100 mg/kg per day. Half the patients in the study will be on a dosage that is closer to the low end of the range, and half will be on a dosage that is closer to the high end. Both groups will be switched for one month to deferiprone DR tablets at approximately the same total daily dosage that they have been taking for Ferriprox.

Study Design

• Study Type: Interventional
• Actual Enrollment: 30 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Parallel AssignmentParallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Safety and Acceptability of Deferiprone Delayed Release Tablets in Patients With Systemic Iron Overload
• Actual Study Start Date: Mar 6, 2019
• Actual Primary Completion Date: Dec 4, 2019
• Actual Study Completion Date: Dec 19, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Low dosage Patients in this group will receive a total daily dosage of deferiprone DR tablets that is closer to 75 mg/kg/day. The total dosage will be divided into two equal parts, taken about 12 hours apart.	Drug: Deferiprone DR tablets 1000 mg (Low dosage); Deferiprone DR tablets 1000 mg
Experimental: High dosage Patients in this group will receive a total daily dosage of deferiprone DR tablets that is closer to 100 mg/kg/day. The total dosage will be divided into two equal parts, taken about 12 hours apart.	Drug: Deferiprone DR tablets 1000 mg (High dosage); Deferiprone DR tablets 1000 mg

Outcome Measures

Primary Outcome Measures

1. The Percentage of Patients in Each Treatment Group Who Experience Post-dose Increases in Liver Enzyme Levels That Are Considered a Safety Concern. [Day 28]

   Levels of the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST) will be assessed throughout the study to determine if any patients have post-dose increases that are considered to be a safety concern. The criteria for being considered a safety concern are meeting one of the following: For a patient whose level was within the normal range at baseline, the criterion is reaching a value of 5 times the upper limit of normal (ULN) For a patient whose level was above the ULN at baseline, the criterion is reaching either 5 times the baseline value or 10 x ULN

Secondary Outcome Measures

1. The Percentage of Patients in Each Treatment Group Who Report Post-dose Occurrences of Gastrointestinal (GI) Distress. [Day 28]

   Patients will be asked to report any events of GI distress during the study, such as nausea, vomiting, diarrhea, abdominal pain, and dyspepsia.

2. The Percentage of Patients in Each Group Who Indicate That They Prefer the Deferiprone DR Formulation Over the Immediate-release Formulation. [Day 28]

   At the end of the study, patients will complete a questionnaire to indicate which formulation they prefer.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Male or female aged ≥ 18 years.

2. Diagnosis of thalassemia syndrome, sickle cell disease, or other disorder requiring a regular regimen of red blood cell transfusions.

3. On a stable regimen (≥3 months) of Ferriprox tablets for the treatment of systemic iron overload.

4. Absolute neutrophil count ≥1.5 x 10^9/L at screening.

5. A record of at least 12 measured alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels.

Exclusion Criteria:

1. Receipt of any iron chelator other than Ferriprox (i.e., combination therapy) in the last 3 months, or planning to receive it at any time during the period of the study.

2. ALT and/or AST value > 5 times the upper limit of normal (ULN) at screening

3. Active case of hepatitis B or C at screening.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Ann & Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois	United States	60611
2	New York Presbyterian Hospital/Weill Cornell Medical Center	New York	New York	United States	10065
3	St.Paul's Hospital	Vancouver	British Columbia	Canada	V6Z 1Y6
4	National and Kapodistrian University of Athens, Aghia Sophia Children's Hospital	Goudí	Athens	Greece	11527
5	San Luigi Gonzaga University Hospital Reparto Microcitemie-Pediatria	Orbassano (TO)	Regione Gonzole	Italy	10043

Sponsors and Collaborators

• ApoPharma

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 10, 2018

More Information

Publications

None provided.

• Responsible Party: ApoPharma
• ClinicalTrials.gov Identifier: NCT03802916
• Other Study ID Numbers: LA61-0218
• First Posted: Jan 14, 2019
• Last Update Posted: Jul 16, 2021
• Last Verified: Jun 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by ApoPharma: iron overload; chelation; deferiprone; Ferriprox
• Additional relevant MeSH terms: Iron Overload; Deferiprone

Study Results

Participant Flow

Arm/Group Title	Low Dosage	High Dosage
Arm/Group Description	Patients in this group will receive a total daily dosage of deferiprone DR tablets that is closer to 75 mg/kg/day. The total dosage will be divided into two equal parts, taken about 12 hours apart. Deferiprone DR tablets 1000 mg (Low dosage): Deferiprone DR tablets 1000 mg	Patients in this group will receive a total daily dosage of deferiprone DR tablets that is closer to 100 mg/kg/day. The total dosage will be divided into two equal parts, taken about 12 hours apart. Deferiprone DR tablets 1000 mg (High dosage): Deferiprone DR tablets 1000 mg
Period Title: Overall Study
STARTED	15	15
COMPLETED	15	13
NOT COMPLETED	0	2

Baseline Characteristics

Arm/Group Title	Low Dosage	High Dosage	Total
Arm/Group Description	Patients in this group will receive a total daily dosage of deferiprone DR tablets that is closer to 75 mg/kg/day. The total dosage will be divided into two equal parts, taken about 12 hours apart. Deferiprone DR tablets 1000 mg (Low dosage): Deferiprone DR tablets 1000 mg	Patients in this group will receive a total daily dosage of deferiprone DR tablets that is closer to 100 mg/kg/day. The total dosage will be divided into two equal parts, taken about 12 hours apart. Deferiprone DR tablets 1000 mg (High dosage): Deferiprone DR tablets 1000 mg	Total of all reporting groups
Overall Participants	15	14	29
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	41.9 (9.9)	40.4 (6.8)	41.1 (8.4)
Sex: Female, Male (Count of Participants)
Female	6 40%	7 50%	13 44.8%
Male	9 60%	7 50%	16 55.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	1 7.1%	1 3.4%
Not Hispanic or Latino	15 100%	13 92.9%	28 96.6%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	2 13.3%	0 0%	2 6.9%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	13 86.7%	13 92.9%	26 89.7%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	1 7.1%	1 3.4%
Region of Enrollment (participants) [Number]
Greece	3 20%	5 35.7%	8 27.6%
Canada	3 20%	0 0%	3 10.3%
United States	1 6.7%	2 14.3%	3 10.3%
Italy	8 53.3%	7 50%	16 55.2%
Level of liver enzymes at baseline for low-dosage group (units per liter) [Mean (Standard Deviation) ]
Baseline ALT	29.60 (19.88)	29.60 (19.88)
Baseline AST	27.53 (10.00)	27.53 (10.00)
Level of liver enzymes at baseline for high-dosage group (units per liter) [Mean (Standard Deviation) ]
Baseline ALT	38.29 (22.43)	38.29 (22.43)
Baseline AST	28.50 (11.39)	28.50 (11.39)

Outcome Measures

1. Primary Outcome

Title	The Percentage of Patients in Each Treatment Group Who Experience Post-dose Increases in Liver Enzyme Levels That Are Considered a Safety Concern.
Description	Levels of the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST) will be assessed throughout the study to determine if any patients have post-dose increases that are considered to be a safety concern. The criteria for being considered a safety concern are meeting one of the following: For a patient whose level was within the normal range at baseline, the criterion is reaching a value of 5 times the upper limit of normal (ULN) For a patient whose level was above the ULN at baseline, the criterion is reaching either 5 times the baseline value or 10 x ULN
Time Frame	Day 28

Outcome Measure Data

Analysis Population Description

One patient in the high-dosage group withdrew before providing any evaluable data

Arm/Group Title	Low Dosage	High Dosage
Arm/Group Description	Evaluable patients who received the lower dosage of deferiprone	Evaluable patients who received the higher dosage of deferiprone
Measure Participants	15	14
Patients with elevated ALT of clinical concern	0 0%	0 0%
Patients with elevated AST of clinical concern	0 0%	0 0%

2. Secondary Outcome

Title	The Percentage of Patients in Each Treatment Group Who Report Post-dose Occurrences of Gastrointestinal (GI) Distress.
Description	Patients will be asked to report any events of GI distress during the study, such as nausea, vomiting, diarrhea, abdominal pain, and dyspepsia.
Time Frame	Day 28

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Low Dosage	High Dosage
Arm/Group Description	Evaluable patients who received the lower dosage of deferiprone	Evaluable patients who received the higher dosage of deferiprone
Measure Participants	15	14
Count of Participants [Participants]	3 20%	3 21.4%

3. Secondary Outcome

Title	The Percentage of Patients in Each Group Who Indicate That They Prefer the Deferiprone DR Formulation Over the Immediate-release Formulation.
Description	At the end of the study, patients will complete a questionnaire to indicate which formulation they prefer.
Time Frame	Day 28

Outcome Measure Data

Analysis Population Description

One of the evaluable patients withdrew before completing the questionnaire

Arm/Group Title	Low Dosage	High Dosage
Arm/Group Description	Patients who completed the questionnaire	Patients who completed the questionnaire
Measure Participants	15	13
Count of Participants [Participants]	13 86.7%	13 92.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Low Dosage
	Comments	One-sample proportion test to determine if the overall preference for deferiprone DR was greater than chance (i.e., a 50% preference for each formulation)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0074
	Comments	A p-value was calculated for the one-sample proportion test.
	Method	One-sample proportion test
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	High Dosage
	Comments	One-sample proportion test to determine if the overall preference for deferiprone DR was greater than chance (i.e., a 50% preference for each formulation)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments	A p-value was calculated for the one-sample proportion test.
	Method	One-sample proportion test
	Comments

Adverse Events

Time Frame	Baseline to Day 28
Arm/Group Title	Low Dosage		High Dosage
Arm/Group Description	Evaluable patients who received the lower dosage of deferiprone		Evaluable patients who received the higher dosage of deferiprone
All Cause Mortality
	Low Dosage		High Dosage
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/14 (0%)
Serious Adverse Events
	Low Dosage		High Dosage
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/14 (0%)
Other (Not Including Serious) Adverse Events
	Low Dosage		High Dosage
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/15 (66.7%)		9/14 (64.3%)
Ear and labyrinth disorders
Ear pain	1/15 (6.7%)	1	1/14 (7.1%)	1
Eye disorders
Blepharitis	0/15 (0%)	0	2/14 (14.3%)	2
Gastrointestinal disorders
Abdominal pain upper	1/15 (6.7%)	1	0/14 (0%)	0
Diarrhoea	0/15 (0%)	0	3/14 (21.4%)	3
Dyspepsia	1/15 (6.7%)	1	0/14 (0%)	0
Nausea	1/15 (6.7%)	1	0/14 (0%)	0
Vomiting	1/15 (6.7%)	1	0/14 (0%)	0
General disorders
Pyrexia	1/15 (6.7%)	1	1/14 (7.1%)	1
Infections and infestations
Conjunctivitis	0/15 (0%)	0	1/14 (7.1%)	1
Pharyngitis	0/15 (0%)	0	1/14 (7.1%)	1
Injury, poisoning and procedural complications
Joint injury	2/15 (13.3%)	2	0/14 (0%)	0
Road traffic accident	1/15 (6.7%)	1	0/14 (0%)	0
Investigations
Alanine aminotransferase increased	0/15 (0%)	0	1/14 (7.1%)	2
Neutrophil count decreased	1/15 (6.7%)	1	0/14 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	3/15 (20%)	5	1/14 (7.1%)	1
Back pain	1/15 (6.7%)	1	1/14 (7.1%)	1
Groin pain	0/15 (0%)	0	1/14 (7.1%)	1
Musculoskeletal pain	1/15 (6.7%)	1	0/14 (0%)	0
Nervous system disorders
Headache	3/15 (20%)	4	3/14 (21.4%)	5
Migraine	1/15 (6.7%)	2	0/14 (0%)	0
Sciatica	1/15 (6.7%)	1	1/14 (7.1%)	1
Psychiatric disorders
Anxiety	1/15 (6.7%)	1	0/14 (0%)	0
Renal and urinary disorders
Renal colic	0/15 (0%)	0	1/14 (7.1%)	1
Reproductive system and breast disorders
Dysmenorrhoea	0/15 (0%)	0	1/14 (7.1%)	1
Respiratory, thoracic and mediastinal disorders
Cough	0/15 (0%)	0	1/14 (7.1%)	1
Dyspnoea	1/15 (6.7%)	1	0/14 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.