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The Sponsor (Amicus Therapeutics) terminated this study for logistical reasons.
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Study to evaluate the long-term safety, tolerability, and pharmacodynamics (PD) of migalastat hydrochloride (HCl) (migalastat) in participants with Fabry disease
This was a long-term open-label study of migalastat in participants with Fabry disease who were previously enrolled in a Phase 2 study of migalastat (FAB-CL-201 [NCT00214500], FAB-CL-202 [NCT00283959], FAB-CL-203 [NCT00283933], or FAB-CL-204 [NCT00304512]). Participants could enter this extension study immediately upon completion of participation in their previous study of migalastat, or at a later time point. Thus, some participants did not necessarily have continuous treatment with migalastat from the end of the original study to the time of enrollment into this extension study. Participants who enrolled before Protocol Amendment 2 received migalastat 150 milligrams (mg) orally once every other day (QOD). After the amendment, these participants entered a dose escalation period (DEP) at their next scheduled visit. During the DEP, participants received migalastat 250 mg (once daily [QD] for 3 days and 4 days off per week) for the first 2 months. If there were no safety concerns, the dose was then increased to 500 mg QD for 3 days and 4 days off per week). Participants received 500 mg (QD for 3 days and 4 days off per week) for up to 10 months, depending on the approval date of the protocol amendments at each site. An interim review of safety and PD data was performed after all enrolled participants had completed at least 4 months of treatment in the DEP. After the review, the dose and regimen of migalastat was returned to 150 mg QOD for all participants, except those who were on another dose as previously agreed by the investigator and medical monitor.
The sponsor (Amicus Therapeutics) discontinued Study FAB-CL-205 for logistical reasons and not due to either safety concerns or lack of efficacy. Participants who were ongoing in Study FAB-CL-205 at the time of discontinuation were offered participation in another open-label, long-term treatment study of migalastat (AT1001-041 [NCT01458119]). Participants who did not enroll in Study AT1001-041 were contacted by telephone or another suitable method approximately 1 month after the End of Study (EOS) visit to inquire about adverse events and concomitant medications.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Migalastat | Experimental | Migalastat was administered orally, 150 mg QOD, 250 mg QD for 3 days, 4 days off per week for 2 months, or 500 mg QD for 3 days, 4 days off per week for up to 10 months, depending on the approval date of the protocol amendments at each site. Participants received migalastat for up to 56 months. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| migalastat HCl | Drug |
|
|
| Measure | Description | Time Frame |
|---|---|---|
| Number Of Participants Who Experienced Severe Treatment-emergent Adverse Events (TEAEs) | A TEAE was defined as any adverse event (AE) with start date on or after administration of study drug or pre-existing conditions that worsened on or after the start of the first study drug administration (on Day 1). A severe AE was defined as an AE that was incapacitating and required medical intervention. The number of participants who experienced one or more severe TEAEs after dosing on Day 1 through End of Study (EOS) or follow-up (for participants who did not enroll in Study AT1001-041) are presented. A summary of serious and all other non-serious AEs regardless of causality is located in the Reported Adverse Events module. | Day 1 (after dosing) through EOS (up to 56 months) or follow-up (28 days after EOS) |
| Measure | Description | Time Frame |
|---|---|---|
| Absolute Change From Baseline In α-Galactosidase A (α-Gal A) Activity In Leukocytes To Month 42 | The activity of the α-Gal A enzyme was measured in leukocyte lysate by a validated fluorometric assay method, using 4-methylumbelliferone as a reference. The activity values obtained were normalized to protein (measured using a colorimetric assay). Baseline was defined as the last non-missing pre-treatment value for each participant in his or her respective preceding migalastat Phase 2 study. A negative change from Baseline indicates that α-Gal A activity decreased. α-Gal A activity levels are presented for Baseline and Month 42. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Medical Monitor, Clinical Research | Amicus Therapeutics | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Decatur | Georgia | 30033 | United States | |||
This study included a dose escalation period (DEP), in which migalastat was administered at 250 milligrams (mg) for 2 months. If there were no safety concerns the dose was increased to 500 mg for up to 10 months, depending on the date of amendment approval. Before and after the DEP, all but 1 participant (post-DEP 300 mg instead) received 150 mg.
An open label, long-term extension study for participants who completed one of 4 preceding Phase 2 studies (FAB-CL-201 [NCT00214500], FAB-CL-202 [NCT00283959], FAB-CL-203 [NCT00283933], or FAB-CL-204 [NCT00304512]). Participants could enter this study directly upon completion of the previous study or at a later point.
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| ID | Title | Description |
|---|---|---|
| FG000 | Migalastat | Participants received migalastat 150 mg given orally once every other day (QOD) before and after the DEP. During the DEP participants received 250 mg once daily (QD) for 3 days, 4 days off per week for 2 months then 500 mg QD for 3 days, 4 days off per week for up to 10 months, depending on the approval date of the protocol amendments at each site. One participant received migalastat 300 mg (QD for 3 days and 4 days off per week) until the end of the study. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Baseline, Month 42 |
| Pharmacokinetics Of Migalastat As Assessed By Plasma Concentration | The concentration of migalastat was evaluated in plasma following a dose of 250 mg and 500 mg. Blood samples were taken at trough (predose or Time 0; just prior to the third dose during a 3 day on, 4 days off dosing regimen) and at peak (3 hr postdose; after the third dose during a 3 day on, 4 days off dosing regimen) during the Day 1 (250 mg) and Month 2 (500 mg) visits. This outcome presents the lowest and highest concentrations of migalastat measured in any of the participants for predose and 3 hr postdose. | 0 (predose on Day 1; start of DEP), 3 hr (postdose at Month 2; during DEP]) |
| New York |
| New York |
| 10016 |
| United States |
| Dallas | Texas | 78226 | United States |
| Parkville | Australia |
| Porto Alegre | Brazil |
| Garches | France |
| London | United Kingdom |
| Salford | United Kingdom |
| Safety Population | All participants who received at least 1 dose of study drug |
|
| Pharmacodynamic (PD) Population | Received study drug and had a baseline measurement and at least 1 postbaseline PD measure |
|
| Amenable Population; Men | Amenable mutations based on the clinical trial (CT) Human Embryonic Kidney (HEK) assay |
|
| Amenable Population; Women | Amenable mutations based on the CT-HEK assay |
|
| Non-amenable Population; Men | Those without mutant forms of α-Gal A responsive to migalastat treatment based on the CT-HEK assay |
|
| Non-amenable Population; Women | Those without mutant forms of α-Gal A responsive to migalastat treatment based on the CT-HEK assay |
|
| COMPLETED |
|
| NOT COMPLETED |
|
|
All participants who received at least 1 dose of study drug.
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| ID | Title | Description |
|---|---|---|
| BG000 | Migalastat | Participants received migalastat 150 mg given orally QOD before and after the DEP. During the DEP participants received 250 mg QD for 3 days, 4 days off per week for 2 months then 500 mg QD for 3 days, 4 days off per week for up to 10 months, depending on the approval date of the protocol amendments at each site. One participant received migalastat 300 mg (QD for 3 days and 4 days off per week) until the end of the study. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | years |
| |||||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Number Of Participants Who Experienced Severe Treatment-emergent Adverse Events (TEAEs) | A TEAE was defined as any adverse event (AE) with start date on or after administration of study drug or pre-existing conditions that worsened on or after the start of the first study drug administration (on Day 1). A severe AE was defined as an AE that was incapacitating and required medical intervention. The number of participants who experienced one or more severe TEAEs after dosing on Day 1 through End of Study (EOS) or follow-up (for participants who did not enroll in Study AT1001-041) are presented. A summary of serious and all other non-serious AEs regardless of causality is located in the Reported Adverse Events module. | Safety Population: all participants who received at least 1 dose of study drug. | Posted | Count of Participants | Participants | Day 1 (after dosing) through EOS (up to 56 months) or follow-up (28 days after EOS) |
|
|
| ||||||||||||||||||||||||||
| Secondary | Absolute Change From Baseline In α-Galactosidase A (α-Gal A) Activity In Leukocytes To Month 42 | The activity of the α-Gal A enzyme was measured in leukocyte lysate by a validated fluorometric assay method, using 4-methylumbelliferone as a reference. The activity values obtained were normalized to protein (measured using a colorimetric assay). Baseline was defined as the last non-missing pre-treatment value for each participant in his or her respective preceding migalastat Phase 2 study. A negative change from Baseline indicates that α-Gal A activity decreased. α-Gal A activity levels are presented for Baseline and Month 42. | PD Population: all participants who received at least 1 dose of study drug and who had a baseline measurement and at least 1 postbaseline PD measure. | Posted | Mean | Standard Deviation | nanomoles (nm)/hour (hr)/mg protein | Baseline, Month 42 |
| |||||||||||||||||||||||||||
| Secondary | Pharmacokinetics Of Migalastat As Assessed By Plasma Concentration | The concentration of migalastat was evaluated in plasma following a dose of 250 mg and 500 mg. Blood samples were taken at trough (predose or Time 0; just prior to the third dose during a 3 day on, 4 days off dosing regimen) and at peak (3 hr postdose; after the third dose during a 3 day on, 4 days off dosing regimen) during the Day 1 (250 mg) and Month 2 (500 mg) visits. This outcome presents the lowest and highest concentrations of migalastat measured in any of the participants for predose and 3 hr postdose. | Safety Population: all participants who received at least 1 dose of study drug. | Posted | Number | nanograms/milliliter | 0 (predose on Day 1; start of DEP), 3 hr (postdose at Month 2; during DEP]) |
|
|
Day 1 after dosing through EOS (up to 56 months) or follow-up (28 days after EOS). Follow-up was not required for participants who enrolled in Study AT1001-041.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Migalastat | Participants received migalastat 150 mg given orally QOD before and after the DEP. During the DEP participants received 250 mg QD for 3 days, 4 days off per week for 2 months then 500 mg QD for 3 days, 4 days off per week for up to 10 months, depending on the approval date of the protocol amendments at each site. One participant received migalastat 300 mg (QD for 3 days and 4 days off per week) until the end of the study. | 7 | 23 | 23 | 23 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Atrial Fibrillation | Cardiac disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Atrial Flutter | Cardiac disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Atrioventricular Block | Cardiac disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Cardiac Failure Congestive | Cardiac disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Ventricular Fibrillation | Cardiac disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Hyperthyroidism | Endocrine disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Dyspepsia | Gastrointestinal disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Sensation of Foreign Body | General disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Ankle Fracture | Injury, poisoning and procedural complications | MedDRA (12.1) | Systematic Assessment |
| |
| Post Procedural Haemorrhage | Injury, poisoning and procedural complications | MedDRA (12.1) | Systematic Assessment |
| |
| Dehydration | Metabolism and nutrition disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Malnutrition | Metabolism and nutrition disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Transient Ischaemic Attack | Nervous system disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Cerebrovascular Accident | Nervous system disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Syncope | Nervous system disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Epistaxis | Respiratory, thoracic and mediastinal disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Pneumonia Aspiration | Respiratory, thoracic and mediastinal disorders | MedDRA (12.1) | Systematic Assessment |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Influenza | Infections and infestations | MedDRA (12.1) | Systematic Assessment |
| |
| Nasopharyngitis | Infections and infestations | MedDRA (12.1) | Systematic Assessment |
| |
| Sinusitis | Infections and infestations | MedDRA (12.1) | Systematic Assessment |
| |
| Upper respiratory tract infection | Infections and infestations | MedDRA (12.1) | Systematic Assessment |
| |
| Urinary tract infection | Infections and infestations | MedDRA (12.1) | Systematic Assessment |
| |
| Cystitis | Infections and infestations | MedDRA (12.1) | Systematic Assessment |
| |
| Lower respiratory tract infection | Infections and infestations | MedDRA (12.1) | Systematic Assessment |
| |
| Rhinitis | Infections and infestations | MedDRA (12.1) | Systematic Assessment |
| |
| Abdominal pain upper | Gastrointestinal disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Diarrhoea | Gastrointestinal disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Abdominal pain | Gastrointestinal disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Gastrooesophageal reflux disease | Gastrointestinal disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Vomiting | Gastrointestinal disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Abdominal distension | Gastrointestinal disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Abdominal pain lower | Gastrointestinal disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Constipation | Gastrointestinal disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Dry mouth | Gastrointestinal disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Nausea | Gastrointestinal disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Myalgia | Musculoskeletal and connective tissue disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Flank pain | Musculoskeletal and connective tissue disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Muscle spasms | Musculoskeletal and connective tissue disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Joint swelling | Musculoskeletal and connective tissue disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Muscle twitching | Musculoskeletal and connective tissue disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Muscular weakness | Musculoskeletal and connective tissue disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Musculoskeletal chest pain | Musculoskeletal and connective tissue disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Musculoskeletal pain | Musculoskeletal and connective tissue disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Neck pain | Musculoskeletal and connective tissue disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Osteoarthritis | Musculoskeletal and connective tissue disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Fatigue | General disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Oedema peripheral | General disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Pyrexia | General disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Asthenia | General disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Chest pain | General disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Influenza like illness | General disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Irritability | General disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Pain | General disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Headache | Nervous system disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Dizziness | Nervous system disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Paraesthesia | Nervous system disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Migraine | Nervous system disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Alanine aminotransferase increased | Investigations | MedDRA (12.1) | Systematic Assessment |
| |
| Platelet count increased | Investigations | MedDRA (12.1) | Systematic Assessment |
| |
| Weight increased | Investigations | MedDRA (12.1) | Systematic Assessment |
| |
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Oropharyngeal pain | Respiratory, thoracic and mediastinal disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Epistaxis | Respiratory, thoracic and mediastinal disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Sinus congestion | Respiratory, thoracic and mediastinal disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Palpitations | Cardiac disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Sinus bradycardia | Cardiac disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Fall | Injury, poisoning and procedural complications | MedDRA (12.1) | Systematic Assessment |
| |
| Limb injury | Injury, poisoning and procedural complications | MedDRA (12.1) | Systematic Assessment |
| |
| Post procedural haematuria | Injury, poisoning and procedural complications | MedDRA (12.1) | Systematic Assessment |
| |
| Dermal cyst | Skin and subcutaneous tissue disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Dry skin | Skin and subcutaneous tissue disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Rash | Skin and subcutaneous tissue disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Vertigo | Ear and labyrinth disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Insomnia | Psychiatric disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Depression | Psychiatric disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Anxiety | Psychiatric disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Haematuria | Renal and urinary disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Vision blurred | Eye disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Vitamin d deficiency | Metabolism and nutrition disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Lymphadenopathy | Blood and lymphatic system disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Fabry's disease | Congenital, familial and genetic disorders | MedDRA (12.1) | Systematic Assessment |
|
The investigator can only publish the results from this trial provided they supply the sponsor (or authorized entity) a copy of any proposed publication for review. If requested, the investigator will remove information deemed confidential or proprietary by the sponsor and will withhold publication for an additional period of time to allow the sponsor to take appropriate measures to establish and preserve its proprietary rights.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Amicus Therapeutics | Medical Affairs | +1-877-426-4287 (877-4-AMICUS) | MedInfoUSA@amicusrx.com |
| ID | Term |
|---|---|
| D000795 | Fabry Disease |
| ID | Term |
|---|---|
| D013106 | Sphingolipidoses |
| D020140 | Lysosomal Storage Diseases, Nervous System |
| D020739 | Brain Diseases, Metabolic, Inborn |
| D001928 | Brain Diseases, Metabolic |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D059345 | Cerebral Small Vessel Diseases |
| D002561 | Cerebrovascular Disorders |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D040181 | Genetic Diseases, X-Linked |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D008661 | Metabolism, Inborn Errors |
| D008064 | Lipidoses |
| D008052 | Lipid Metabolism, Inborn Errors |
| D016464 | Lysosomal Storage Diseases |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D052439 | Lipid Metabolism Disorders |
Not provided
Not provided
| ID | Term |
|---|---|
| C090092 | migalastat |
| C525167 | larazotide acetate |
Not provided
Not provided
Not provided
Amenable participants were those with mutant forms of α-Gal A determined to be responsive to migalastat treatment based on the CT-HEK assay. Migalastat was administered orally, 150 mg QOD before and after the DEP. During the DEP participants received 250 mg QD for 3 days, 4 days off per week for 2 months then 500 mg QD for 3 days, 4 days off per week for up to 10 months, depending on the approval date of the protocol amendments at each site. |
| OG002 | Non-amenable Population; Men | Non-amenable participants were those without mutant forms of α-Gal A as determined by the CT-HEK assay. Migalastat was administered orally, 150 mg QOD before and after the DEP. During the DEP participants received 250 mg QD for 3 days, 4 days off per week for 2 months then 500 mg QD for 3 days, 4 days off per week for up to 10 months, depending on the approval date of the protocol amendments at each site. |
| OG003 | Non-amenable Population; Women | Non-amenable participants were those without mutant forms of α-Gal A as determined by the CT-HEK assay. Migalastat was administered orally, 150 mg QOD before and after the DEP. During the DEP participants received 250 mg QD for 3 days, 4 days off per week for 2 months then 500 mg QD for 3 days, 4 days off per week for up to 10 months, depending on the approval date of the protocol amendments at each site. |
|
|
|
| Title | Measurements |
|---|---|
|