Safety and Pharmacodynamic Study of an Oral Iron Chelator Given for 6 Months to Patients With Iron Overload

• Sponsor: Shire (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01186419
• Collaborator: (none)
• Enrollment: 51
• Locations: 9
• Arms: 2
• Actual Duration (Months): 28.9
• Patients Per Site: 5.7
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this research study is to evaluate the safety of two doses of FBS0701, a new oral iron chelator, and its effectiveness in clearing iron from the liver. FBS0701 is a medication taken by mouth that causes the body to get rid of iron. Iron chelators are used in patients with β-thalassemia and other forms of anemia who experience iron overload - iron increases in the body as a result of regularly required blood transfusions. Patients who qualify will be randomized to receive one of two doses of FBS0701 for up to 24 weeks (6 months) with a total study duration of up to 33 weeks. These patients will be eligible to participate in a dosing extension for up to 72 weeks. The maximum duration of dosing will be up to 96 weeks. The safety of patients will be monitored frequently during the study by physical exams, ECGs, and blood tests. To assess the amount of iron in the liver and heart, each patient must undergo 6 MRI scans during the study. Patients will not need to stay in the hospital for this study but will need to visit the outpatient clinic up to 28 times over the 96 week period. Patients currently taking an iron chelator will be required to stop for a total of up to 26 weeks. The results of this study will help to determine if FBS0701 may be effective as an iron chelator.

Condition or Disease	Intervention/Treatment	Phase
Transfusional Iron Overload; Beta-thalassemia	Drug: SPD602 (FBS0701, SSP-004184)	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 51 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2, 24 Week, Randomized, Open Label, Multi-Center Study to Assess the Safety, Tolerability, and Pharmacodynamics of FBS0701 in the Treatment of Chronic Iron Overload Requiring Chelation Therapy, With a 72 Week Dosing Extension
• Actual Study Start Date: Aug 13, 2010
• Actual Primary Completion Date: Jan 8, 2013
• Actual Study Completion Date: Jan 8, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: SPD602 (16mg)	Drug: SPD602 (FBS0701, SSP-004184); Oral FBS0701 taken one time daily for up to 96 weeks.
Experimental: SPD602 (32mg)	Drug: SPD602 (FBS0701, SSP-004184); Oral FBS0701 taken one time daily for up to 96 weeks.

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Liver Iron Concentration (LIC) at 96 Weeks [Baseline and 96 weeks]

   LIC was determined by R2 Magnetic Resonance Imaging (MRI).

Secondary Outcome Measures

1. Maximum Plasma Concentration (Cmax) of SPD602 [92 weeks]

   Cmax is a term that refers to the maximum (or peak) concentration that a drug achieves in the body after the drug has been administered.

2. Area Under The Steady-state Plasma Concentration-time Curve (AUC) of SPD602 [92 weeks]

   AUC can be used as a measure of drug exposure. It is derived from drug concentration and time so it gives a measure of how much and how long a drug stays in a body.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Transfusional iron overload due to: hereditary anemias such as sickle cell disease, β-thalassemia and Diamond-Blackfan anemia; acquired anemias such as Myelodysplastic Syndrome and other forms of bone marrow failure. Patients must also be transfusion-dependent and require chronic treatment with deferoxamine, deferasirox, and/or deferiprone.

• Willing to discontinue all existing iron chelation therapies throughout study period.

• Serum ferritin greater than 500 ng/mL at Screening.

• Baseline liver iron concentration and cardiac MRI T2* per protocol requirements.

• Mean of the previous three pre-transfusion hemoglobin concentrations greater than or equal to 7.5 g/dL.

• Agrees to use an approved method of contraception throughout study period.

Exclusion Criteria:

• As a result of medical review, physical examination or Screening investigations, the Principal Investigator considers the patient unfit for the study.

• Non-elective hospitalization within the 30 days prior to Baseline testing. (Patients with sickle cell anemia who are admitted to the hospital for management of sickle crisis pain whose uncomplicated hospital course was four days or less and who, 14 days prior to Baseline testing, have returned to their previous health status are acceptable.)

• Evidence of clinically relevant oral, cardiovascular, gastrointestinal, hepatic, renal, endocrine, pulmonary, neurologic, psychiatric, immunologic, bone marrow or skin disorder as determined by the Investigator.

• Evidence of significant renal insufficiency; possible examples include: serum creatinine above the upper limit of normal, proteinuria greater than 2 gm per day or calculated creatinine clearance of less than 60 mL/minute.

• Cardiac left ventricular ejection fraction outside of protocol requirements.

• Known sensitivity to magnesium stearate, croscarmellose sodium or FBS0701.

• Platelet count below 100,000/µL and/or absolute neutrophil count less than 1500/mm3 at Screening and <50% at Baseline testing by MRI

• Alkaline phosphatase, AST or ALT outside of protocol requirements.

• Liver Function Tests: ALT >5 times the local upper limit of normal on two occasions in the previous 12 months or ALT at Screening >200 IU/L

• Use of any investigational agent within the 30 days prior to the Baseline testing.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital and Research Center of Oakland	Oakland	California	United States	94609
2	Children's Hospital of Boston	Boston	Massachusetts	United States	02115
3	Ospedale Regionale Microcitemie	Cagliari		Italy
4	Centro della Microcitemia e delle Anemie Congenite	Genoa		Italy
5	Thalassemia Center San Luigi Hospital	Orbassano		Italy
6	Siriraj Hospital, Mahidol University	Bangkok		Thailand
7	Pediatric Hematology, Ege University Hospital	Izmir		Turkey
8	University College London Hospital	London		United Kingdom
9	Whittington Hospital	London		United Kingdom

Sponsors and Collaborators

• Shire

Investigators

• Study Director: Study Director, Takeda

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Shire
• ClinicalTrials.gov Identifier: NCT01186419
• Other Study ID Numbers: SPD602-201; 2010-019645-25; FBS0701-CTP-04
• First Posted: Aug 23, 2010
• Last Update Posted: Jun 10, 2021
• Last Verified: May 1, 2021

• Keywords provided by Shire: Beta-thalassemia; Sickle cell anemia; Transfusional iron overload; Iron overload; Iron chelation
• Additional relevant MeSH terms: Thalassemia; beta-Thalassemia; Iron Overload

Study Results

Participant Flow

Arm/Group Title	SPD602 16 mg/kg/Day	SPD602 32 mg/kg/Day
Arm/Group Description	Participants received SPD602 orally once daily for up to 96 weeks. At Week 24, the iron clearing activity of SPD602 was assessed for each participant and the dose may have been adjusted to a higher or lower dose if the clinical response was deemed insufficient or too robust, respectively (maximum dose=60mg/kg/day; minimum dose=8mg/kg/day). Participants not dose adjusted at Week 24 may also have had later dose adjustments to a higher or lower dose.	Participants received SPD602 orally once daily for up to 96 weeks. At Week 24, the iron clearing activity of SPD602 was assessed for each participant and the dose may have been adjusted to a higher or lower dose if the clinical response was deemed insufficient or too robust, respectively (maximum dose=60mg/kg/day; minimum dose=8mg/kg/day). Participants not dose adjusted at Week 24 may also have had later dose adjustments to a higher or lower dose.
Period Title: Overall Study
STARTED	24	27
COMPLETED	17	18
NOT COMPLETED	7	9

Baseline Characteristics

Arm/Group Title	SPD602 16 mg/kg/Day	SPD602 32 mg/kg/Day	Total
Arm/Group Description	Participants received SPD602 orally once daily for up to 96 weeks. At Week 24, the iron clearing activity of SPD602 was assessed for each participant and the dose may have been adjusted to a higher or lower dose if the clinical response was deemed insufficient or too robust, respectively (maximum dose=60mg/kg/day; minimum dose=8mg/kg/day). Participants not dose adjusted at Week 24 may also have had later dose adjustments to a higher or lower dose.	Participants received SPD602 orally once daily for up to 96 weeks. At Week 24, the iron clearing activity of SPD602 was assessed for each participant and the dose may have been adjusted to a higher or lower dose if the clinical response was deemed insufficient or too robust, respectively (maximum dose=60mg/kg/day; minimum dose=8mg/kg/day). Participants not dose adjusted at Week 24 may also have had later dose adjustments to a higher or lower dose.	Total of all reporting groups
Overall Participants	24	27	51
Age (Count of Participants)
<=18 years	0 0%	1 3.7%	1 2%
Between 18 and 65 years	24 100%	26 96.3%	50 98%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	28.7 (8.60)	28.4 (7.11)	28.5 (7.77)
Sex: Female, Male (Count of Participants)
Female	12 50%	14 51.9%	26 51%
Male	12 50%	13 48.1%	25 49%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Liver Iron Concentration (LIC) at 96 Weeks
Description	LIC was determined by R2 Magnetic Resonance Imaging (MRI).
Time Frame	Baseline and 96 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set, defined as all subjects in the Safety Set who had at least 1 post-baseline primary efficacy assessment. The Safety Set was defined as all subjects who received any amount of investigational product.

Arm/Group Title	SPD602
Arm/Group Description	Participants received SPD602 orally once daily for up to 96 weeks.
Measure Participants	26
Mean (Standard Deviation) [mg/g]	-1.75 (4.839)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	SPD602
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0765
	Comments
	Method	t-test, 2 sided
	Comments

2. Secondary Outcome

Title	Maximum Plasma Concentration (Cmax) of SPD602
Description	Cmax is a term that refers to the maximum (or peak) concentration that a drug achieves in the body after the drug has been administered.
Time Frame	92 weeks

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) Analysis Set, defined as all subjects in the Safety Set for whom the primary PK data were considered sufficient and interpretable. The Safety Set was defined as all subjects who received any amount of investigational product.

Arm/Group Title	SPD602
Arm/Group Description	Participants received SPD602 orally once daily for up to 96 weeks.
Measure Participants	5
Mean (Standard Deviation) [ng/ml]	25702.7 (4448.06)

3. Secondary Outcome

Title	Area Under The Steady-state Plasma Concentration-time Curve (AUC) of SPD602
Description	AUC can be used as a measure of drug exposure. It is derived from drug concentration and time so it gives a measure of how much and how long a drug stays in a body.
Time Frame	92 weeks

Outcome Measure Data

Analysis Population Description

PK Analysis Set, defined as all subjects in the Safety Set for whom the primary PK data were considered sufficient and interpretable. The Safety Set was defined as all subjects who received any amount of investigational product.

Arm/Group Title	SPD602
Arm/Group Description	Participants received SPD602 orally once daily for up to 96 weeks.
Measure Participants	5
Mean (Standard Deviation) [ng*hr/ml]	62998.6 (23094.72)

Adverse Events

Arm/Group Title	SPD602 16 mg/kg/d		SPD602 32 mg/kg/d
Arm/Group Description	Participants received SPD602 orally once daily for up to 96 weeks. At Week 24, the iron clearing activity of SPD602 was assessed for each participant and the dose may have been adjusted to a higher or lower dose if the clinical response was deemed insufficient or too robust, respectively (maximum dose=60mg/kg/day; minimum dose=8mg/kg/day). Participants not dose adjusted at Week 24 may also have had later dose adjustments to a higher or lower dose.		Participants received SPD602 orally once daily for up to 96 weeks. At Week 24, the iron clearing activity of SPD602 was assessed for each participant and the dose may have been adjusted to a higher or lower dose if the clinical response was deemed insufficient or too robust, respectively (maximum dose=60mg/kg/day; minimum dose=8mg/kg/day). Participants not dose adjusted at Week 24 may also have had later dose adjustments to a higher or lower dose.
All Cause Mortality
	SPD602 16 mg/kg/d		SPD602 32 mg/kg/d
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	SPD602 16 mg/kg/d		SPD602 32 mg/kg/d
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/24 (12.5%)		2/27 (7.4%)
Congenital, familial and genetic disorders
Sickle cell anemia with crisis	1/24 (4.2%)	4	0/27 (0%)	0
Gastrointestinal disorders
Vomiting	1/24 (4.2%)	1	0/27 (0%)	0
General disorders
Chest discomfort	0/24 (0%)	0	1/27 (3.7%)	1
Metabolism and nutrition disorders
Diabetes mellitus	0/24 (0%)	0	1/27 (3.7%)	1
Musculoskeletal and connective tissue disorders
Back pain	0/24 (0%)	0	1/27 (3.7%)	1
Nervous system disorders
Hypoaesthesia	1/24 (4.2%)	1	0/27 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea exertional	0/24 (0%)	0	1/27 (3.7%)	1
Other (Not Including Serious) Adverse Events
	SPD602 16 mg/kg/d		SPD602 32 mg/kg/d
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	24/24 (100%)		26/27 (96.3%)
Cardiac disorders
Palpitations	2/24 (8.3%)	2	3/27 (11.1%)	4
Tachycardia	0/24 (0%)	0	2/27 (7.4%)	2
Congenital, familial and genetic disorders
Sickle cell anaemia with crisis	2/24 (8.3%)	7	0/27 (0%)	0
Ear and labyrinth disorders
Ear pain	0/24 (0%)	0	2/27 (7.4%)	2
Eye disorders
Conjunctivitis	2/24 (8.3%)	2	2/27 (7.4%)	2
Ocular icterus	0/24 (0%)	0	3/27 (11.1%)	3
Gastrointestinal disorders
Abdominal pain	0/24 (0%)	0	5/27 (18.5%)	5
Abdominal pain upper	4/24 (16.7%)	4	5/27 (18.5%)	7
Colitis	1/24 (4.2%)	1	2/27 (7.4%)	3
Constipation	1/24 (4.2%)	2	4/27 (14.8%)	6
Diarrhea	1/24 (4.2%)	2	3/27 (11.1%)	3
Dyspepsia	3/24 (12.5%)	3	1/27 (3.7%)	1
Enteritis	0/24 (0%)	0	3/27 (11.1%)	3
Flatulence	5/24 (20.8%)	7	3/27 (11.1%)	3
Nausea	3/24 (12.5%)	3	3/27 (11.1%)	3
Toothache	0/24 (0%)	0	3/27 (11.1%)	4
Vomiting	2/24 (8.3%)	3	2/27 (7.4%)	2
General disorders
Asthenia	3/24 (12.5%)	4	1/27 (3.7%)	4
Fatigue	2/24 (8.3%)	2	1/27 (3.7%)	2
Influenza like illness	2/24 (8.3%)	3	4/27 (14.8%)	9
Pyrexia	4/24 (16.7%)	7	3/27 (11.1%)	6
Oedema peripheral	0/24 (0%)	0	2/27 (7.4%)	2
Infections and infestations
Bronchitis	2/24 (8.3%)	2	2/27 (7.4%)	2
Gastroenteritis	3/24 (12.5%)	3	3/27 (11.1%)	3
Influenza	2/24 (8.3%)	5	6/27 (22.2%)	7
Nasopharyngitis	5/24 (20.8%)	5	4/27 (14.8%)	4
Pharyngitis	5/24 (20.8%)	5	5/27 (18.5%)	6
Pharyngotonsillitis	1/24 (4.2%)	1	2/27 (7.4%)	3
Respiratory tract infection viral	2/24 (8.3%)	2	2/27 (7.4%)	2
Sinusitis	3/24 (12.5%)	3	1/27 (3.7%)	2
Upper respiratory tract infection	5/24 (20.8%)	7	7/27 (25.9%)	13
Viral infection	1/24 (4.2%)	1	2/27 (7.4%)	2
Cystitis	2/24 (8.3%)	2	0/27 (0%)	0
Oral herpes	2/24 (8.3%)	2	0/27 (0%)	0
Injury, poisoning and procedural complications
Transfusion reaction	1/24 (4.2%)	1	2/27 (7.4%)	2
Joint injury	0/24 (0%)	0	2/27 (7.4%)	3
Joint sprain	2/24 (8.3%)	2	0/27 (0%)	0
Skin laceration	0/24 (0%)	0	2/27 (7.4%)	2
Contusion	2/24 (8.3%)	2	0/27 (0%)	0
Investigations
Blood creatinine increased	0/24 (0%)	0	3/27 (11.1%)	3
Cardiac murmur	0/24 (0%)	0	4/27 (14.8%)	8
Gamma-glutamyltransferase increased	1/24 (4.2%)	4	3/27 (11.1%)	3
Transaminases increased	2/24 (8.3%)	2	5/27 (18.5%)	7
Metabolism and nutrition disorders
Decreased appetite	2/24 (8.3%)	3	0/27 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	3/24 (12.5%)	5	2/27 (7.4%)	3
Back pain	7/24 (29.2%)	10	4/27 (14.8%)	11
Musculoskeletal pain	3/24 (12.5%)	3	0/27 (0%)	0
Bone pain	0/24 (0%)	0	2/27 (7.4%)	2
Muscle spasms	2/24 (8.3%)	2	0/27 (0%)	0
Pain in extremity	0/24 (0%)	0	2/27 (7.4%)	2
Nervous system disorders
Headache	8/24 (33.3%)	24	9/27 (33.3%)	15
Paraesthesia	2/24 (8.3%)	5	4/27 (14.8%)	5
Hypoaesthesia	2/24 (8.3%)	9	0/27 (0%)	0
Psychiatric disorders
Insomnia	0/24 (0%)	0	2/27 (7.4%)	2
Renal and urinary disorders
Chromaturia	1/24 (4.2%)	1	2/27 (7.4%)	2
Respiratory, thoracic and mediastinal disorders
Cough	3/24 (12.5%)	4	1/27 (3.7%)	1
Oropharyngeal pain	4/24 (16.7%)	10	4/27 (14.8%)	7
Skin and subcutaneous tissue disorders
Rash papular	0/24 (0%)	0	2/27 (7.4%)	2

Limitations/Caveats

Only data from all subjects (ie, total) are presented because dose adjustments that occurred after Week 24 obviated the meaningful interpretation of data presented by the original 16 and 32 mg/kg/day dose groups.

More Information

Certain Agreements

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

If a multicenter publication is not submitted within twelve (12) months after conclusion, abandonment or termination of the Study at all sites, or after Sponsor confirms there shall be no multicenter Study publication, the Institution and/or such Principal Investigator may publish the results from the Institution site individually.