TIRCON-EXT: Long-term Deferiprone Treatment in Patients With Pantothenate Kinase-Associated Neurodegeneration

• Sponsor: ApoPharma (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02174848
• Collaborator: (none)
• Enrollment: 68
• Locations: 4
• Arm: 1
• Duration (Months): 45.5
• Patients Per Site: 17
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

Patients with PKAN will be treated with the iron chelator deferiprone for 18 months. Only patients who have completed the earlier study TIRCON2012V1 (NCT01741532), a double-blind placebo-controlled trial in which participants were randomized to receive either deferiprone or placebo for 18 months, are eligible to enroll.

Condition or Disease	Intervention/Treatment	Phase
Pantothenate Kinase-Associated Neurodegeneration	Drug: Deferiprone oral solution	Phase 3

Detailed Description

TIRCON2012V1-EXT is a multi-center, single-arm, open-label study. All patients who completed the earlier study TIRCON2012V1 (NCT01741532) are eligible to take part. In the initial study, patients were randomized in a 2:1 ratio to receive 18 months of treatment with either the iron chelator deferiprone or placebo, respectively. In this extension study, all participants will receive deferiprone for 18 months. Thus, depending on which product was received earlier, patients will be on deferiprone for a total of either 1.5 years or 3 years. As in the earlier study, assessments will be carried out every six months to look at the safety of the drug and to see if patients are showing any improvement in dystonia and other symptoms of PKAN.

Study Design

• Study Type: Interventional
• Actual Enrollment: 68 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: All participants in this study received the same intervention.All participants in this study received the same intervention.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Long-term Safety and Efficacy Study of Deferiprone in Patients With Pantothenate Kinase-Associated Neurodegeneration (PKAN)
• Study Start Date: Jun 1, 2014
• Actual Primary Completion Date: Mar 16, 2018
• Actual Study Completion Date: Mar 16, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Deferiprone All patients will receive deferiprone oral solution.	Drug: Deferiprone oral solution; Deferiprone oral solution at a dosage of up to 15 mg per kilogram of body weight, twice a day; Other Names: DFP

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Adverse Events [18 months]

   Safety and tolerability were assessed based on changes in: frequency of adverse events (AEs), frequency of serious adverse events (SAEs), and discontinuation due to AEs. No statistical comparison between the groups was conducted as all participants received the same study product.

Secondary Outcome Measures

1. Change in Score on the BAD Scale -- Comparison of Treatment Groups Over Each Study [Baseline and Month 18 of each study]

   The Barry-Albright Dystonia (BAD) scale is an instrument for rating the severity of dystonia in eight body regions. The individual scores are summed to provide a total score that ranges from 0 to 32; the higher the score, the more severe the dystonia. Patients were assessed for the change in total BAD score over the course of both the initial study (during which one group received placebo and the other received deferiprone) and the extension study (during which both groups received deferiprone).

2. Change in Score on the BAD Scale -- Comparison of Placebo-DFP Patients Across Studies [Baseline and Month 18 of each study]

   The Barry-Albright Dystonia (BAD) scale is an instrument for rating the severity of dystonia in eight body regions. The individual scores are summed to provide a total score that ranges from 0 to 32; the higher the score, the more severe the dystonia. Patients were assessed for the change in total BAD score over the course of each study.

3. Change in Score on the BAD Scale -- Comparison of DFP-DFP Patients Across Studies [Baseline and Month 18 of each study]

   The Barry-Albright Dystonia (BAD) scale is an instrument for rating the severity of dystonia in eight body regions. The individual scores are summed to provide a total score that ranges from 0 to 32; the higher the score, the more severe the dystonia. Patients were assessed for the change in total BAD score over the course of the study.

4. Proportion of Patients With Improved or Unchanged BAD Score [Month 18 of each study]

   Patients were deemed to be responders if their BAD total score either improved or remained unchanged from baseline, with baseline being the start of each study for the placebo-DFP group and the start of the initial study for the DFP-DFP group

5. Patient Global Impression of Improvement (PGI-I) Comparison of Placebo-DFP Patients Across Studies [Month 18 of each study]

   The Patient Global Impression of Improvement (PGI-I) is a global index used to rate the response of a condition to a therapy. Patients were asked at each post-baseline visit to rate their overall condition since the start of the extension study on a 7-point rating scale: 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 5 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Completed study TIRCON2012V1

Exclusion Criteria:

• Withdrew from the study TIRCON2012V1 for reasons of safety

• Plan to participate in another clinical trial at any time from the day of enrolment until 30 days post-treatment in the current study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCSF Benioff Children's Hospital Oakland	Oakland	California	United States	94609
2	Klinikum der Universität München	Munich		Germany	80336
3	Foundation Neurological Institute C. Besta	Milan		Italy	20133
4	Newcastle University Institute of Human Genetics	Newcastle Upon Tyne		United Kingdom	NE1 3BZ

Sponsors and Collaborators

• ApoPharma

Investigators

• Principal Investigator: Elliott Vichinsky, MD, UCSF Benioff Children's Hospital Oakland
• Principal Investigator: Thomas Klopstock, MD, Klinikum der Universität München
• Principal Investigator: Nardo Nardocci, MD, Foundation Neurological Institute C. Besta
• Principal Investigator: Patrick Chinnery, MD, Newcastle University Institute of Human Genetics

Study Documents (Full-Text)

• Statistical Analysis Plan - Apr 9, 2018
• Study Protocol - Aug 20, 2014

More Information

Publications

None provided.

• Responsible Party: ApoPharma
• ClinicalTrials.gov Identifier: NCT02174848
• Other Study ID Numbers: TIRCON2012V1-EXT; 2012-000845-11
• First Posted: Jun 26, 2014
• Last Update Posted: Aug 25, 2020
• Last Verified: Aug 1, 2020

• Keywords provided by ApoPharma: Pantothenate Kinase-Associated Neurodegeneration; PKAN; Neurodegeneration with Brain Iron Accumulation; NBIA; Deferiprone; Ferriprox
• Additional relevant MeSH terms: Pantothenate Kinase-Associated Neurodegeneration; Nerve Degeneration; Deferiprone

Study Results

Participant Flow

Arm/Group Title	Placebo-DFP	DFP-DFP
Arm/Group Description	Patients in this group had been randomized to placebo treatment in the TIRCON2012V1 study and were then switched to deferiprone in the extension study. Accordingly, they received up to 18 months of deferiprone treatment over the duration of the two studies.	Patients in this group had been randomized to deferiprone treatment in the TIRCON2012V1 study and then continued on deferiprone in the extension study. Accordingly, they received up to 36 months of deferiprone treatment over the duration of the two studies.
Period Title: Overall Study
STARTED	24	44
Provided Post-baseline Efficacy Data	19	43
COMPLETED	17	38
NOT COMPLETED	7	6

Baseline Characteristics

Arm/Group Title	Placebo-DFP	DFP-DFP	Total
Arm/Group Description	Patients who received 18 months of placebo treatment in the TIRCON2012V1 study and were then switched to deferiprone in the extension study, so received up to 18 months of deferiprone treatment.	Patients who received 18 months of deferiprone treatment in the TIRCON2012V1 study and continued to receive it in the extension study, so received up to 36 months of deferiprone treatment.	Total of all reporting groups
Overall Participants	24	44	68
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	19.9 (13.0)	22.4 (9.6)	21.5 (10.9)
Sex: Female, Male (Count of Participants)
Female	14 58.3%	16 36.4%	30 44.1%
Male	10 41.7%	28 63.6%	38 55.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	1 4.2%	3 6.8%	4 5.9%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	22 91.7%	41 93.2%	63 92.6%
More than one race	1 4.2%	0 0%	1 1.5%
Unknown or Not Reported	0 0%	0 0%	0 0%
BAD score at baseline (units on a scale) [Mean (Standard Deviation) ]
BAD score at baseline of initial study	16.0 (8.0)	19.4 (8.1)	18.3 (8.2)
BAD score at baseline of extension study	20.4 (8.2)	21.3 (7.6)	21.0 (7.7)

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Adverse Events
Description	Safety and tolerability were assessed based on changes in: frequency of adverse events (AEs), frequency of serious adverse events (SAEs), and discontinuation due to AEs. No statistical comparison between the groups was conducted as all participants received the same study product.
Time Frame	18 months

Outcome Measure Data

Analysis Population Description

Safety population

Arm/Group Title	Placebo-DFP	DFP-DFP
Arm/Group Description	Patients in this group had been randomized to placebo treatment in the TIRCON2012V1 study and were then switched to deferiprone in the extension study. Accordingly, they received up to 18 months of deferiprone treatment.	Patients in this group had been randomized to deferiprone treatment in the TIRCON2012V1 study and then continued on deferiprone in the extension study. Accordingly, they received up to 36 months of deferiprone treatment.
Measure Participants	24	44
Number of patients with at least one AE	22 91.7%	42 95.5%
Number of patients with at least one SAE	12 50%	14 31.8%
Number of patients who withdrew due to an AE	2 8.3%	1 2.3%

2. Secondary Outcome

Title	Change in Score on the BAD Scale -- Comparison of Treatment Groups Over Each Study
Description	The Barry-Albright Dystonia (BAD) scale is an instrument for rating the severity of dystonia in eight body regions. The individual scores are summed to provide a total score that ranges from 0 to 32; the higher the score, the more severe the dystonia. Patients were assessed for the change in total BAD score over the course of both the initial study (during which one group received placebo and the other received deferiprone) and the extension study (during which both groups received deferiprone).
Time Frame	Baseline and Month 18 of each study

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo-DFP	DFP-DFP
Arm/Group Description	Patients in this group had been randomized to placebo treatment in the TIRCON2012V1 study and were then switched to deferiprone in the extension study. Accordingly, they received up to 18 months of deferiprone treatment over the duration of the two studies.	Patients in this group had been randomized to deferiprone treatment in the TIRCON2012V1 study and then continued on deferiprone in the extension study. Accordingly, they received up to 36 months of deferiprone treatment over the duration of the two studies.
Measure Participants	19	43
Change in BAD score over initial study	4.4 (4.8)	1.9 (3.2)
Change in BAD score over extension study	1.4 (3.7)	1.4 (2.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo-DFP, DFP-DFP
	Comments	This comparison is for the initial study, during which patients in the placebo-DFP group received placebo and patients in the DFP-DFP group received deferiprone.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0500
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo-DFP, DFP-DFP
	Comments	This comparison is for the extension study, during which patients in both groups received deferiprone.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9781
	Comments
	Method	t-test, 2 sided
	Comments

3. Secondary Outcome

Title	Change in Score on the BAD Scale -- Comparison of Placebo-DFP Patients Across Studies
Description	The Barry-Albright Dystonia (BAD) scale is an instrument for rating the severity of dystonia in eight body regions. The individual scores are summed to provide a total score that ranges from 0 to 32; the higher the score, the more severe the dystonia. Patients were assessed for the change in total BAD score over the course of each study.
Time Frame	Baseline and Month 18 of each study

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo-DFP in Initial Study	Placebo-DFP in Extension Study
Arm/Group Description	During the initial study, patients in the placebo-DFP group received 18 months of treatment with placebo	During the extension study, patients in the placebo-DFP group received up to 18 months of treatment with deferiprone
Measure Participants	19	19
Mean (Standard Deviation) [score on a scale]	4.4 (4.8)	1.4 (3.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo-DFP, DFP-DFP
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0206
	Comments
	Method	paired t-test
	Comments

4. Secondary Outcome

Title	Change in Score on the BAD Scale -- Comparison of DFP-DFP Patients Across Studies
Description	The Barry-Albright Dystonia (BAD) scale is an instrument for rating the severity of dystonia in eight body regions. The individual scores are summed to provide a total score that ranges from 0 to 32; the higher the score, the more severe the dystonia. Patients were assessed for the change in total BAD score over the course of the study.
Time Frame	Baseline and Month 18 of each study

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	DFP-DFP Group in Initial Study	DFP-DFP Group in Extension Study
Arm/Group Description	During the initial study, patients in the DFP-DFP group received 18 months of treatment with deferiprone	During the extension study, patients in the DFP-DFP group received up to an additional 18 months of treatment with deferiprone
Measure Participants	43	43
Mean (Standard Deviation) [score on a scale]	1.9 (3.2)	1.4 (2.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo-DFP, DFP-DFP
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2684
	Comments
	Method	paired t-test
	Comments

5. Secondary Outcome

Title	Proportion of Patients With Improved or Unchanged BAD Score
Description	Patients were deemed to be responders if their BAD total score either improved or remained unchanged from baseline, with baseline being the start of each study for the placebo-DFP group and the start of the initial study for the DFP-DFP group
Time Frame	Month 18 of each study

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo-DFP	DFP-DFP
Arm/Group Description	Patients in this group had been randomized to placebo treatment in the TIRCON2012V1 study and were then switched to deferiprone in the extension study. Accordingly, they received up to 18 months of deferiprone treatment.	Patients in this group had been randomized to deferiprone treatment in the TIRCON2012V1 study and then continued on deferiprone in the extension study. Accordingly, they received up to 36 months of deferiprone treatment.
Measure Participants	19	43
Completion of initial study	3 12.5%	17 38.6%
Completion of 18 months of deferiprone treatment	9 37.5%	17 38.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo-DFP, DFP-DFP
	Comments	This comparison is for the initial study, during which patients in the placebo-DFP group received placebo and patients in the DFP-DFP group received deferiprone
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0821
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo-DFP, DFP-DFP
	Comments	For the placebo-DFP group, the comparison is of the scores at the start vs. the end of the extension study; for the DFP-DFP group, the comparison is of the scores at the start vs. the end of the initial study
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5885
	Comments
	Method	t-test, 2 sided
	Comments

6. Secondary Outcome

Title	Patient Global Impression of Improvement (PGI-I) Comparison of Placebo-DFP Patients Across Studies
Description	The Patient Global Impression of Improvement (PGI-I) is a global index used to rate the response of a condition to a therapy. Patients were asked at each post-baseline visit to rate their overall condition since the start of the extension study on a 7-point rating scale: 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse.
Time Frame	Month 18 of each study

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo-DFP in Initial Study	Placebo-DFP in Extension Study
Arm/Group Description	During the initial study, patients in the placebo-DFP group received 18 months of treatment with placebo	During the extension study, patients in the placebo-DFP group received up to 18 months of treatment with deferiprone
Measure Participants	19	19
Mean (Standard Deviation) [score on a scale]	4.4 (1.5)	4.7 (1.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo-DFP, DFP-DFP
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3306
	Comments
	Method	t-test, 2 sided
	Comments

Adverse Events

Time Frame	Safety data were collected from the time of first dose until the end of the study (up to 18 months)
Arm/Group Title	All Patients
Arm/Group Description	All participants received deferiprone during the extension study
All Cause Mortality
	All Patients
	Affected / at Risk (%)	# Events
Total	2/68 (2.9%)
Serious Adverse Events
	All Patients
	Affected / at Risk (%)	# Events
Total	33/68 (48.5%)
Blood and lymphatic system disorders
Neutropenia	4/68 (5.9%)	7
Cardiac disorders
Cyanosis	1/68 (1.5%)	1
Tachycardia	1/68 (1.5%)	1
Gastrointestinal disorders
Constipation	1/68 (1.5%)	1
Gastritis	1/68 (1.5%)	1
Intestinal dilatation	1/68 (1.5%)	1
Intestinal obstruction	1/68 (1.5%)	1
Oesophagitis	1/68 (1.5%)	1
Salivary hypersecretion	1/68 (1.5%)	1
Vomiting	1/68 (1.5%)	1
General disorders
Condition aggravated	1/68 (1.5%)	1
Medical device site inflammation	1/68 (1.5%)	1
Multiple organ dysfunction syndrome	1/68 (1.5%)	1
Obstruction	1/68 (1.5%)	1
Pyrexia	3/68 (4.4%)	3
Infections and infestations
Bacterial disease carrier	1/68 (1.5%)	1
Bronchitis	2/68 (2.9%)	2
Device related infection	1/68 (1.5%)	1
Infective glossitis	1/68 (1.5%)	1
Peritonitis	1/68 (1.5%)	1
Pneumonia	2/68 (2.9%)	3
Respiratory tract infection	1/68 (1.5%)	1
Urinary tract infection	1/68 (1.5%)	1
Viral infection	1/68 (1.5%)	1
Wound infection	2/68 (2.9%)	2
Injury, poisoning and procedural complications
Chemical eye injury	1/68 (1.5%)	1
Clavicle fracture	1/68 (1.5%)	1
Toxicity to various agents	1/68 (1.5%)	1
Unintentional medical device removal	1/68 (1.5%)	1
Wound	1/68 (1.5%)	1
Investigations
Device function test	1/68 (1.5%)	1
Physical examination	1/68 (1.5%)	1
Weight decreased	1/68 (1.5%)	1
Musculoskeletal and connective tissue disorders
Bursitis	1/68 (1.5%)	1
Nervous system disorders
Dystonia	8/68 (11.8%)	8
Headache	1/68 (1.5%)	1
Hyporesponsive to stimuli	1/68 (1.5%)	1
Loss of consciousness	1/68 (1.5%)	1
Oromandibular dystonia	1/68 (1.5%)	1
Somnolence	1/68 (1.5%)	1
Syncope	1/68 (1.5%)	1
Product Issues
Device dislocation	1/68 (1.5%)	1
Device malfunction	1/68 (1.5%)	1
Device stimulation issue	1/68 (1.5%)	1
Psychiatric disorders
Agitation	1/68 (1.5%)	2
Renal and urinary disorders
Urinary bladder rupture	1/68 (1.5%)	1
Respiratory, thoracic and mediastinal disorders
Aspiration	1/68 (1.5%)	1
Choking	1/68 (1.5%)	1
Cough	1/68 (1.5%)	1
Pneumonia aspiration	1/68 (1.5%)	1
Pneumothorax	1/68 (1.5%)	1
Respiratory disorder	1/68 (1.5%)	1
Respiratory failure	1/68 (1.5%)	1
Surgical and medical procedures
Colostomy closure	1/68 (1.5%)	1
Dental operation	1/68 (1.5%)	1
Gastrointestinal tube insertion	1/68 (1.5%)	1
Gastrostomy	4/68 (5.9%)	4
Hip surgery	1/68 (1.5%)	1
Intrathecal pump insertion	1/68 (1.5%)	1
Jejunostomy	1/68 (1.5%)	1
Medical device battery replacement	2/68 (2.9%)	2
Medical device change	2/68 (2.9%)	2
Medical device implantation	3/68 (4.4%)	3
Medical device removal	1/68 (1.5%)	1
Tracheostomy	1/68 (1.5%)	5
Tracheostomy tube removal	1/68 (1.5%)	1
Wound treatment	1/68 (1.5%)	1
Vascular disorders
Thrombosis	1/68 (1.5%)	2
Other (Not Including Serious) Adverse Events
	All Patients
	Affected / at Risk (%)	# Events
Total	66/68 (97.1%)
Blood and lymphatic system disorders
Anemias	12/68 (17.6%)	27
Gastrointestinal disorders
Abdominal pain upper	8/68 (11.8%)	16
Diarrhoea	4/68 (5.9%)	6
Dysphagia	8/68 (11.8%)	8
Nausea	5/68 (7.4%)	5
Vomiting	10/68 (14.7%)	13
General disorders
Condition aggravated	17/68 (25%)	25
Pain	5/68 (7.4%)	5
Pyrexia	20/68 (29.4%)	64
Infections and infestations
Bronchitis	6/68 (8.8%)	30
Influenza	4/68 (5.9%)	4
Nasopharyngitis	11/68 (16.2%)	22
Upper respiratory tract infection	13/68 (19.1%)	19
Urinary tract infection	6/68 (8.8%)	8
Injury, poisoning and procedural complications
Contusion	5/68 (7.4%)	5
Laceration	8/68 (11.8%)	20
Investigations
Body temperature increased	4/68 (5.9%)	4
Neutrophil count decreased	10/68 (14.7%)	26
Serum ferritin decreased	18/68 (26.5%)	25
Metabolism and nutrition disorders
Iron deficiency	11/68 (16.2%)	11
Pain in extremity	14/68 (20.6%)	26
Musculoskeletal and connective tissue disorders
Arthralgia	11/68 (16.2%)	12
Back pain	4/68 (5.9%)	4
Muscle spasms	8/68 (11.8%)	11
Nervous system disorders
Aphasia	5/68 (7.4%)	6
Ataxia	4/68 (5.9%)	4
Balance disorder	5/68 (7.4%)	5
Dystonia	32/68 (47.1%)	74
Headache	19/68 (27.9%)	64
Somnolence	6/68 (8.8%)	8
Tremor	4/68 (5.9%)	7
Psychiatric disorders
Agitation	5/68 (7.4%)	13
Respiratory, thoracic and mediastinal disorders
Cough	12/68 (17.6%)	19
Oropharyngeal pain	10/68 (14.7%)	11
Rhinorrhoea	6/68 (8.8%)	8
Skin and subcutaneous tissue disorders
Rash	5/68 (7.4%)	5

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Sponsor retained title to and the right to publish all documentation, records, raw data, specimens or other work product generated in connection with the trial. Such publications shall not be made without the prior written consent of Sponsor. Neither Party will use the other Party's name in connection with any publication or promotion without the other Party's prior written consent. However, Sponsor has the right to publish appropriate information in order to satisfy regulatory requirements.