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Terminated due to low enrollment and unclear pharmacologic effect in available pharmacodynamic data (not due to any safety concerns).
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| Name | Class |
|---|---|
| Genzyme, a Sanofi Company | INDUSTRY |
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Methylmalonic acidemia (MMA) is a rare genetic disorder caused by mutations in the gene for mitochondrial enzyme methylmalonyl-CoA mutase (MCM) or in one of the genes for adenosylcobalamin (AdoCbl). Lack of these proteins causes toxic elevations of methylmalonic acid (MMacid) in blood, urine, and other tissues. A specific type of mutation, called a nonsense (premature stop codon) mutation, is the cause of the disease in approximately 5% to 20% of participants with mutations in the MCM gene, and approximately 20% to >50% of participants with mutations in one of the AdoCbl genes. Ataluren is an orally delivered, investigational drug that acts to overcome the effects of the premature stop codon, potentially enabling the production of functional MCM/AdoCbl. This study is a Phase 2a trial evaluating the safety and activity of ataluren in participants with MMA due to a nonsense mutation. The main purpose of this study is to understand whether ataluren can safely decrease MMacid levels.
In this study, participants with MMA due to a nonsense mutation will be administered an investigational drug called ataluren. Evaluation procedures to determine if a participant qualifies for the study will be performed within 14 days prior to the start of drug administration. Eligible participants who elect to enroll in the study will then participate in 2 drug administration and follow-up periods. Within the first period, ataluren will be taken 3 times per day with meals for 28 days at doses of 5 milligrams/kilograms (mg/kg) (morning), 5 mg/kg (midday), and 10 mg/kg (evening); there will then be an interval of approximately 21 days without ataluren. Within the second period, ataluren will be taken 3 times per day with meals for 28 days at doses of 10 mg/kg (morning), 10 mg/kg (midday), and 20 mg/kg (evening); there will then be an interval of approximately 14 days without ataluren. During the study, ataluren activity, safety, and pharmacokinetics will be evaluated, and MMacid levels in blood and urine will be measured periodically.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Ataluren | Experimental | Cycle 1: Ataluren treatment will be taken 3 times per day with meals for 28 days at doses of 5 mg/kg (morning), 5 mg/kg (midday), and 10 mg/kg (evening); there will then be an interval of 21 up to 42 days without treatment. Cycle 2: Ataluren treatment will be taken 3 times per day with meals for 28 days at doses of 10 mg/kg (morning), 10 mg/kg (midday), and 20 mg/kg (evening); there will then be an interval of 14 days without treatment. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Ataluren | Drug | Ataluren will be provided as a vanilla-flavored powder to be mixed with water. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Plasma Methylmalonic Acid (MMacid) Levels | Normal plasma MMacid level is <0.27 micromole/liters (umol/L). Plasma samples for MMacid levels were collected after a 2- to 4-hour fast. Plasma MMacid levels were measured by a standard gas chromatography/mass spectroscopy (GC/MS) stable-isotope dilution method. Individual participant values in plasma MMacid levels at Baseline and end-to-treatment (Day 28 and Day 29 [last day of dosing]) in each cycle were recorded. | Baseline and Day 28 and Day 29 (last day of dosing) of Cycles 1 and 2 |
| Measure | Description | Time Frame |
|---|---|---|
| Urinary MMacid Levels | The normal urinary MMacid level is <4 millimole/mole (mmol/mol) creatinine. Urinary samples for MMacid levels were collected after a 2- to 4-hour fast. Urinary MMacid levels were measured by a standard GC/MS stable-isotope dilution method. | Baseline and Day 28 and Day 29 (last day of dosing) of Cycles 1 and 2 |
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Major Inclusion Criteria:
Major Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Jay Barth, MD | PTC Therapeutics | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| ZNA Queen Paola Child Hospital and Provincial Centre for Metabolic Disorders | Antwerp | Belgium | ||||
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 17450125 | Background | Welch EM, Barton ER, Zhuo J, Tomizawa Y, Friesen WJ, Trifillis P, Paushkin S, Patel M, Trotta CR, Hwang S, Wilde RG, Karp G, Takasugi J, Chen G, Jones S, Ren H, Moon YC, Corson D, Turpoff AA, Campbell JA, Conn MM, Khan A, Almstead NG, Hedrick J, Mollin A, Risher N, Weetall M, Yeh S, Branstrom AA, Colacino JM, Babiak J, Ju WD, Hirawat S, Northcutt VJ, Miller LL, Spatrick P, He F, Kawana M, Feng H, Jacobson A, Peltz SW, Sweeney HL. PTC124 targets genetic disorders caused by nonsense mutations. Nature. 2007 May 3;447(7140):87-91. doi: 10.1038/nature05756. Epub 2007 Apr 22. | |
| 17389552 |
| Label | URL |
|---|---|
| PTC Therapeutics' website | View source |
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| ID | Title | Description |
|---|---|---|
| FG000 | Ataluren | Cycle 1: Ataluren treatment was taken 3 times per day with meals for 28 days at doses of 5 milligrams/kilograms (mg/kg) (morning), 5 mg/kg (midday), and 10 mg/kg (evening); there was then an interval of 21 up to 42 days without treatment. Cycle 2: Ataluren treatment was taken 3 times per day with meals for 28 days at doses of 10 mg/kg (morning), 10 mg/kg (midday), and 20 mg/kg (evening); there was then an interval of 14 days without treatment. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Cycle 1 |
| ||||||||||||||||
| Cycle 2 |
|
All randomized participants who received at least 1 dose of study drug.
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| ID | Title | Description |
|---|---|---|
| BG000 | Ataluren | Cycle 1: Ataluren treatment was taken 3 times per day with meals for 28 days at doses of 5 mg/kg (morning), 5 mg/kg (midday), and 10 mg/kg (evening); there was then an interval of 21 up to 42 days without treatment. Cycle 2: Ataluren treatment was taken 3 times per day with meals for 28 days at doses of 10 mg/kg (morning), 10 mg/kg (midday), and 20 mg/kg (evening); there was then an interval of 14 days without treatment. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| 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 | Plasma Methylmalonic Acid (MMacid) Levels | Normal plasma MMacid level is <0.27 micromole/liters (umol/L). Plasma samples for MMacid levels were collected after a 2- to 4-hour fast. Plasma MMacid levels were measured by a standard gas chromatography/mass spectroscopy (GC/MS) stable-isotope dilution method. Individual participant values in plasma MMacid levels at Baseline and end-to-treatment (Day 28 and Day 29 [last day of dosing]) in each cycle were recorded. | All randomized participants who received at least 1 dose of study drug. | Posted | Median | Full Range | umol/L | Baseline and Day 28 and Day 29 (last day of dosing) of Cycles 1 and 2 |
|
Baseline up to Day 112 (end of study follow-up)
All randomized participants who received at least 1 dose of study drug.
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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 | Ataluren | Cycle 1: Ataluren treatment was taken 3 times per day with meals for 28 days at doses of 5 mg/kg (morning), 5 mg/kg (midday), and 10 mg/kg (evening); there was then an interval of 21 up to 42 days without treatment. Cycle 2: Ataluren treatment was taken 3 times per day with meals for 28 days at doses of 10 mg/kg (morning), 10 mg/kg (midday), and 20 mg/kg (evening); there was then an interval of 14 days without treatment. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Glomerular vascular disorder | Renal and urinary disorders | MedDRA 11.1 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Patient Advocacy | PTC Therapeutics, Inc. | 1-866-562-4620 | medinfo@ptcbio.com |
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| ID | Term |
|---|---|
| D000592 | Amino Acid Metabolism, Inborn Errors |
| ID | Term |
|---|---|
| D008661 | Metabolism, Inborn Errors |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D008659 | Metabolic Diseases |
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| ID | Term |
|---|---|
| C515878 | ataluren |
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| Plasma Propionylcarnitine Levels |
Plasma samples for propionylcarnitine levels were evaluated to detect disease activity. The level of propionylcarnitine was measured using gas chromatography and LC/MS-MS. An increase in propionylcarnitine values indicates greater disease activity. |
| Baseline and Day 28 and Day 29 (last day of dosing) of Cycles 1 and 2 |
| Urine Methylcitric Acid Levels | Urine methylcitric acid levels were evaluated to detect disease activity. An increase in methylcitric acid values indicates greater disease activity. | Baseline and Day 28 and Day 29 (last day of dosing) of Cycles 1 and 2 |
| Number of Participants With Adverse Events (AEs) | An AE was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the Investigator on a scale of mild, moderate and severe, with severe as an AE that prevents usual activities. Relationship of AE to treatment was determined by the Investigator. Serious AEs include death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized the participant and required medical intervention to prevent the previously listed serious outcomes. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. | Baseline up to Day 112 (end of study follow-up) |
| Number of Participants With Potentially Clinically Significant Laboratory (Hematology and Biochemistry) Abnormal Results | Hematological and biochemistry data graded according to Common Terminology Criteria for Adverse Events (CTCAE) severity grade (Grade 1 [mild], Grade 2 [moderate], Grade 3 [severe], Grade 4 [life-threatening], or Grade 5 [fatal]). Life-threatening (Grade 4) or severe (Grade 3) laboratory abnormalities were considered clinically significant. Recurrent or persistent moderate (Grade 2) abnormalities were also considered clinically significant in certain circumstances. Hematology assessments: white blood cell count with differential, hemoglobin, hematocrit, other red cell parameters, and platelet count. Biochemistry assessments: sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, magnesium, calcium, phosphorus, uric acid, glucose, total protein, albumin, bilirubin (direct and indirect), aspartate aminotransferase, alanine aminotransferase, glutamyl transferase, creatine kinase, lactate dehydrogenase, alkaline phosphatase, total cholesterol, and triglycerides. | Baseline up to Day 112 (end of study follow-up) |
| Number of Participants With a Metabolic Decompensation Episode | A metabolic decompensation episode is characterized by vomiting, hypotonia, and alteration of consciousness associated with metabolic acidosis and hyperammonemia. | Baseline up to Day 112 (end of study follow-up) |
| Number of Participants Compliant With Study Treatment | For each participant, compliance was described in terms of the proportion of drug actually taken relative to the amount that should have been taken during the time the participant was on study (both Cycle 1 and Cycle 2). | Baseline up to Day 29 of Cycles 1 and 2 |
| Ataluren Plasma Exposure | Validated quantitative methods employing high performance liquid chromatography with tandem mass spectroscopy (HPLC-MS-MS) were used to determine plasma concentrations of unchanged ataluren. The median and full range of the total of all of the ataluren plasma concentrations collected at Baseline and at Day 28 are reported. | Baseline on Day 0 of Cycles 1 and 2 [0 (predose), 1, 2, 3, and 4 hours postdose of the morning dose and 0 (predose) of the midday dose]; Day 28 of Cycles 1 and 2 [0 (predose), 1, 2, 3, and 4 hours postdose of the morning, midday, and evening doses] |
| Hôpital Edouard Herriot |
| Lyon |
| France |
| Necker-Enfants Malades Hospital | Paris | France |
| University Children's Hospital | Düsseldorf | Germany |
| Istituti Clinici di Perfezionamento, Milano | Milan | Italy |
| Federico II University | Naples | Italy |
| University Hospital, Department of Pediatrics | Padova | Italy |
| University Children's Hospital | Zurich | Switzerland |
| Great Ormand Street Hospital | London | United Kingdom |
| Background |
| Hirawat S, Welch EM, Elfring GL, Northcutt VJ, Paushkin S, Hwang S, Leonard EM, Almstead NG, Ju W, Peltz SW, Miller LL. Safety, tolerability, and pharmacokinetics of PTC124, a nonaminoglycoside nonsense mutation suppressor, following single- and multiple-dose administration to healthy male and female adult volunteers. J Clin Pharmacol. 2007 Apr;47(4):430-44. doi: 10.1177/0091270006297140. |
| NOT COMPLETED |
|
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
|
|
| Secondary | Urinary MMacid Levels | The normal urinary MMacid level is <4 millimole/mole (mmol/mol) creatinine. Urinary samples for MMacid levels were collected after a 2- to 4-hour fast. Urinary MMacid levels were measured by a standard GC/MS stable-isotope dilution method. | All randomized participants who received at least 1 dose of study drug. | Posted | Median | Full Range | mmol/mol creatinine | Baseline and Day 28 and Day 29 (last day of dosing) of Cycles 1 and 2 |
|
|
|
| Secondary | Plasma Propionylcarnitine Levels | Plasma samples for propionylcarnitine levels were evaluated to detect disease activity. The level of propionylcarnitine was measured using gas chromatography and LC/MS-MS. An increase in propionylcarnitine values indicates greater disease activity. | All randomized participants who received at least 1 dose of study drug. | Posted | Median | Full Range | umol/L | Baseline and Day 28 and Day 29 (last day of dosing) of Cycles 1 and 2 |
|
|
|
| Secondary | Urine Methylcitric Acid Levels | Urine methylcitric acid levels were evaluated to detect disease activity. An increase in methylcitric acid values indicates greater disease activity. | All randomized participants who received at least 1 dose of study drug. | Posted | Median | Full Range | mmol/mol creatinine | Baseline and Day 28 and Day 29 (last day of dosing) of Cycles 1 and 2 |
|
|
|
| Secondary | Number of Participants With Adverse Events (AEs) | An AE was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the Investigator on a scale of mild, moderate and severe, with severe as an AE that prevents usual activities. Relationship of AE to treatment was determined by the Investigator. Serious AEs include death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized the participant and required medical intervention to prevent the previously listed serious outcomes. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. | All randomized participants who received at least 1 dose of study drug. | Posted | Count of Participants | Participants | Baseline up to Day 112 (end of study follow-up) |
|
|
|
| Secondary | Number of Participants With Potentially Clinically Significant Laboratory (Hematology and Biochemistry) Abnormal Results | Hematological and biochemistry data graded according to Common Terminology Criteria for Adverse Events (CTCAE) severity grade (Grade 1 [mild], Grade 2 [moderate], Grade 3 [severe], Grade 4 [life-threatening], or Grade 5 [fatal]). Life-threatening (Grade 4) or severe (Grade 3) laboratory abnormalities were considered clinically significant. Recurrent or persistent moderate (Grade 2) abnormalities were also considered clinically significant in certain circumstances. Hematology assessments: white blood cell count with differential, hemoglobin, hematocrit, other red cell parameters, and platelet count. Biochemistry assessments: sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, magnesium, calcium, phosphorus, uric acid, glucose, total protein, albumin, bilirubin (direct and indirect), aspartate aminotransferase, alanine aminotransferase, glutamyl transferase, creatine kinase, lactate dehydrogenase, alkaline phosphatase, total cholesterol, and triglycerides. | All randomized participants who received at least 1 dose of study drug. | Posted | Count of Participants | Participants | Baseline up to Day 112 (end of study follow-up) |
|
|
|
| Secondary | Number of Participants With a Metabolic Decompensation Episode | A metabolic decompensation episode is characterized by vomiting, hypotonia, and alteration of consciousness associated with metabolic acidosis and hyperammonemia. | All randomized participants who received at least 1 dose of study drug. | Posted | Count of Participants | Participants | Baseline up to Day 112 (end of study follow-up) |
|
|
|
| Secondary | Number of Participants Compliant With Study Treatment | For each participant, compliance was described in terms of the proportion of drug actually taken relative to the amount that should have been taken during the time the participant was on study (both Cycle 1 and Cycle 2). | All randomized participants who received at least 1 dose of study drug. | Posted | Count of Participants | Participants | Baseline up to Day 29 of Cycles 1 and 2 |
|
|
|
| Secondary | Ataluren Plasma Exposure | Validated quantitative methods employing high performance liquid chromatography with tandem mass spectroscopy (HPLC-MS-MS) were used to determine plasma concentrations of unchanged ataluren. The median and full range of the total of all of the ataluren plasma concentrations collected at Baseline and at Day 28 are reported. | All randomized participants who received at least 1 dose of study drug and had evaluable ataluren plasma exposure data. | Posted | Median | Full Range | microgram/milliliters (μg/mL) | Baseline on Day 0 of Cycles 1 and 2 [0 (predose), 1, 2, 3, and 4 hours postdose of the morning dose and 0 (predose) of the midday dose]; Day 28 of Cycles 1 and 2 [0 (predose), 1, 2, 3, and 4 hours postdose of the morning, midday, and evening doses] |
|
|
|
| 0 |
| 11 |
| 10 |
| 11 |
| Hypercreatininaemia | Renal and urinary disorders | MedDRA 11.1 | Systematic Assessment |
|
| Hypertransaminasaemia | Hepatobiliary disorders | MedDRA 11.1 | Systematic Assessment |
|
| Hypercalcaemia | Metabolism and nutrition disorders | MedDRA 11.1 | Systematic Assessment |
|
| Hypercholesterolaemia | Metabolism and nutrition disorders | MedDRA 11.1 | Systematic Assessment |
|
| Gastroenteritis | Infections and infestations | MedDRA 11.1 | Systematic Assessment |
|
| Abdominal pain | Gastrointestinal disorders | MedDRA 11.1 | Systematic Assessment |
|
| Rhinorrhoea | Respiratory, thoracic and mediastinal disorders | MedDRA 11.1 | Systematic Assessment |
|
| Hypertriglyceridaemia | Metabolism and nutrition disorders | MedDRA 11.1 | Systematic Assessment |
|
| Haematoma | Vascular disorders | MedDRA 11.1 | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA 11.1 | Systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA 11.1 | Systematic Assessment |
|
| Muscle spasms | Musculoskeletal and connective tissue disorders | MedDRA 11.1 | Systematic Assessment |
|
| Muscle strain | Injury, poisoning and procedural complications | MedDRA 11.1 | Systematic Assessment |
|
| Skin discolouration | Skin and subcutaneous tissue disorders | MedDRA 11.1 | Systematic Assessment |
|
| Convulsion | Nervous system disorders | MedDRA 11.1 | Systematic Assessment |
|
| Nasopharyngitis | Infections and infestations | MedDRA 11.1 | Systematic Assessment |
|
| Pyrexia | General disorders | MedDRA 11.1 | Systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA 11.1 | Systematic Assessment |
|
| Flatulence | Gastrointestinal disorders | MedDRA 11.1 | Systematic Assessment |
|
| Rash | Skin and subcutaneous tissue disorders | MedDRA 11.1 | Systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA 11.1 | Systematic Assessment |
|
| Scoliosis | Musculoskeletal and connective tissue disorders | MedDRA 11.1 | Systematic Assessment |
|
| Hypoglycaemia | Metabolism and nutrition disorders | MedDRA 11.1 | Systematic Assessment |
|
| Hypernatraemia | Metabolism and nutrition disorders | MedDRA 11.1 | Systematic Assessment |
|
| Hyperuricaemia | Metabolism and nutrition disorders | MedDRA 11.1 | Systematic Assessment |
|
The Sponsor can review results and/or communications prior to public release and can embargo communications regarding trial results for a period that is up to 180 days from the time submitted to the sponsor for review.
The sponsor may consult with the PI to require changes to the communication or extend the embargo.
| D009750 | Nutritional and Metabolic Diseases |
| Title | Measurements |
|---|---|
|
| Baseline of Cycle 2 |
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| Day 28 of Cycle 2 |
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| Day 29 of Cycle 2 |
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| Title | Measurements |
|---|---|
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| Baseline of Cycle 2 |
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| Day 28 of Cycle 2 |
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| Day 29 of Cycle 2 |
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| Title | Measurements |
|---|---|
|
| Baseline of Cycle 2 |
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| Day 28 of Cycle 2 |
|
| Day 29 of Cycle 2 |
|
| Title | Measurements |
|---|---|
|
| Serious AE |
|
| AE leading to discontinuation |
|
|
| Baseline of Cycle 2 |
|
|
| Day 28 of Cycle 2 |
|
|