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This clinical trial studied the safety and efficacy of asfotase alfa in children with HPP compared to a historical control group.
Asfotase Alfa was formerly referred to as ENB-0040
Hypophosphatasia (HPP) is a life-threatening, genetic, and ultra-rare metabolic disease characterized by defective bone mineralization and impaired phosphate and calcium regulation that can lead to progressive damage to multiple vital organs, including destruction and deformity of bones, profound muscle weakness, seizures, impaired renal function, and respiratory failure. There are no approved disease-modifying treatments for patients with this disease. There is also limited data available on the natural course of this disease over time, particularly in patients with the juvenile-onset form.
Efficacy analyses were prospectively defined in the protocol with a comparison to historical controls. The historical control group came from patients whose characteristics matched as closely as possible the entry criteria for the trial. The control group included all patients who had x-rays within the age range defined by the inclusion criteria of this study (5 to 12 years of age, inclusive, with open growth plates).
The pre-specified plan for analysis was to combine the two asfotase alfa treated groups (asfotase alfa 2 mg/kg subcutaneous (SC) injection three times per week or 3 mg/kg subcutaneous (SC) injection three times per week) and compare them to historical controls.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 2 mg/kg | Active Comparator | 2 mg/kg subcutaneous injection three times per week. |
|
| 3 mg/kg | Active Comparator | 3 mg/kg subcutaneous injection three times per week. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| asfotase alfa | Biological | 2 mg/kg subcutaneous injection three times per week for 6 months. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Change in Rickets Severity on Skeletal Radiographs From Baseline to Week 24 as Measured by the Radiographic Global Impression of Change (RGI-C) Scale | A 7-point RGI-C (radiographic global impression of change) score was used to rate change in rickets severity. Only those patients with a minimum score of +2 indicating substantial healing of rickets) were considered responders. Three pediatric radiologists not affiliated with the conduct of the study performed the ratings. | Baseline and Week 24 |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Osteomalacia - Osteoid Thickness (as Measured by Trans-iliac Crest Bone Biopsy) | Change from Baseline to Week 24 in osteoid thickness. | Baseline and Week 24 |
| Change in Osteomalacia - Osteoid Volume/Bone Volume (as Measured by Trans-iliac Crest Bone Biopsy) |
Not provided
Inclusion Criteria:
Written informed consent from parent or legal guardian prior to participation
Patients > 5 and < 12 years of age with open growth plates at time of enrollment
Tanner stage of 2 or less indicating pre-pubescence
Documented history of HPP, as evidenced by:
25(OH) vitamin D level > 20 ng/mL
Ability of patient and parent/guardian to comply with study requirements
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Shriners Hospital for Children | St Louis | Missouri | 63131 | United States | ||
| The University of Manitoba Health Services Centre |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 18086009 | Background | Millan JL, Narisawa S, Lemire I, Loisel TP, Boileau G, Leonard P, Gramatikova S, Terkeltaub R, Camacho NP, McKee MD, Crine P, Whyte MP. Enzyme replacement therapy for murine hypophosphatasia. J Bone Miner Res. 2008 Jun;23(6):777-87. doi: 10.1359/jbmr.071213. | |
| 32417537 | Derived | Simmons JH, Rush ET, Petryk A, Zhou S, Martos-Moreno GA. Dual X-ray absorptiometry has limited utility in detecting bone pathology in children with hypophosphatasia: A pooled post hoc analysis of asfotase alfa clinical trial data. Bone. 2020 Aug;137:115413. doi: 10.1016/j.bone.2020.115413. Epub 2020 May 14. |
| Label | URL |
|---|---|
| HPP support group | View source |
Not provided
Patients meeting eligibility criteria were randomly assigned to receive 2mg/kg or 3mg/kg of asfotase alfa SC 3 times weekly for 24 weeks.
Patients were recruited to participate in the study from September to December 2009 at investigational sites via posting in clinicaltrials.gov and contact with physicians experienced in the diagnosis and management of HPP. De-identified historical controls were also selected from a natural history database of patients with HPP.
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| ID | Title | Description |
|---|---|---|
| FG000 | 2 mg/kg Asfotase Alfa | 2 mg/kg subcutaneous (SC) injection three times per week. |
| FG001 | 3 mg/kg Asfotase Alfa | 3 mg/kg subcutaneous (SC) injection three times per week. |
| FG002 | Historical Control | De-identified historical control patients (i.e., untreated with asfotase alfa) were selected from a longitudinal natural history database of patients with HPP maintained at Shriner's Hospitals for Children, St. Louis, Missouri. Historical controls must have had at least two sets of wrist and knee radiographs taken between the ages of 5 years, 0 months and 12 years, 0 months with evidence of open growth plates. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Asfotase Alfa 2 mg/kg | 2 mg/kg thrice weekly administered as a subcutaneous (SC) injection |
| BG001 | Asfotase Alfa 3 mg/kg | 3 mg/kg administered thrice weekly as a subcutaneous (SC) injection |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of 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 | Change in Rickets Severity on Skeletal Radiographs From Baseline to Week 24 as Measured by the Radiographic Global Impression of Change (RGI-C) Scale | A 7-point RGI-C (radiographic global impression of change) score was used to rate change in rickets severity. Only those patients with a minimum score of +2 indicating substantial healing of rickets) were considered responders. Three pediatric radiologists not affiliated with the conduct of the study performed the ratings. | ITT population, which included randomized patients that received treatment with asfotase alfa, even if discontinued or lost to follow-up. The last assessment prior to Week 24 is used for missing Week 24 data; patients with no post-baseline assessments imputed as having no change. A historical control group is used for comparison. | Posted | Median | Full Range | units on a scale | Baseline and Week 24 |
|
6 months
Adverse event data for the historical control group were not collected.
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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 | Asfotase Alfa 2 mg/kg | 2 mg/kg thrice weekly administered as a subcutaneous (SC) injection |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Injection site erythema | General disorders | MedDRA 13.0 | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Alexion Pharma GmbH | Alexion Pharma GmbH | (617) 494-1393 | ClinicalTrials@alxn.com |
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| ID | Term |
|---|---|
| D007014 | Hypophosphatasia |
| D001847 | Bone Diseases |
| D012279 | Rickets |
| D010018 | Osteomalacia |
| ID | Term |
|---|---|
| D008664 | Metal Metabolism, Inborn Errors |
| D008661 | Metabolism, Inborn Errors |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
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| ID | Term |
|---|---|
| C570710 | asfotase alfa |
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| asfotase alfa | Biological | 3 mg/kg subcutaneous injection three times per week for 6 months. |
|
|
Change from Baseline to Week 24 in osteoid volume/bone volume (%), calculated as the absolute difference of the Baseline and Week 24 percentages. |
| Baseline and Week 24 |
| Change in Osteomalacia - Mineralization Lag Time (as Measured by Trans-iliac Crest Bone Biopsy) | Change from Baseline to Week 24 in mineralization lag time. | Baseline and Week 24 |
| Change in Height (Z-scores) | Change from Baseline to Week 24 in Height Z-Score. Height Z-Scores assigned based on Centers for Disease Control (CDC) growth charts and methodology. | Baseline and Week 24 |
| Change in Biomarkers of Asfotase Alfa Activity as Measured by Plasma Inorganic Pyrophosphate (PPi) | Change from Baseline to Week 24 in Plasma PPi | Baseline and Week 24 |
| Change in Biomarkers of Asfotase Alfa Activity as Measured by Pyridoxal-5'-Phosphate (PLP) | Change from Baseline to Week 24 in Plasma PLP | Baseline and Week 24 |
| Maximum Serum Concentration of Asfotase Alfa (Cmax). | Maximum serum concentration observed following single dose of asfotase alfa. | Study Week 1 (0 to 48 hours post-dose) |
| Time at Maximum Serum Concentration of Asfotase Alfa (Tmax) | Maximum serum concentration observed following single dose of asfotase alfa. | Study Week 1 (0 to 48 hours post-dose) |
| Area Under Serum Concentration-time Curve to Last Measurable Concentration of Asfotase Alfa (AUCt) | Area under serum concentration-time curve to last measurable concentration following single dose of asfotase alfa. | Study Week 1 (0 to 48 hours post-dose) |
| Maximum Serum Concentration of Asfotase Alfa (Cmax). | Maximum serum concentration observed following multiple doses of asfotase alfa. | Study Week 6 (0 to 48 hours post-dose) |
| Time at Maximum Serum Concentration of Asfotase Alfa (Tmax). | Time at maximum serum concentration observed following multiple doses of asfotase alfa. | Study Week 6 (0 to 48 hours post-dose) |
| Area Under Serum Concentration-time Curve to Last Measurable Concentration of Asfotase Alfa (AUCt) | Area under serum concentration-time curve to last measurable concentration following multiple doses of asfotase alfa. | Study Week 6 (0 to 48 hours post-dose). |
| Winnipeg |
| Manitoba |
| R3A 1S1 |
| Canada |
| 27699270 | Derived | Whyte MP, Madson KL, Phillips D, Reeves AL, McAlister WH, Yakimoski A, Mack KE, Hamilton K, Kagan K, Fujita KP, Thompson DD, Moseley S, Odrljin T, Rockman-Greenberg C. Asfotase alfa therapy for children with hypophosphatasia. JCI Insight. 2016 Jun 16;1(9):e85971. doi: 10.1172/jci.insight.85971. |
| US Hypophosphatasia Group (Soft Bones) | View source |
| Hypophosphatasia Website | View source |
| Hypophosphatasia Website for Healthcare Providers | View source |
| BG002 | Historical Control | De-identified historical controls selected from a natural history database of patients with HPP. |
| BG003 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
De-identified historical controls selected from a natural history database of patients with HPP.
| OG001 | Asfotase Alfa Combined | ITT Population: Asfotase alfa 2 mg/kg subcutaneous (SC) injection three times per week or 3 mg/kg subcutaneous (SC) injection three times per week. |
|
|
|
| Secondary | Change in Osteomalacia - Osteoid Thickness (as Measured by Trans-iliac Crest Bone Biopsy) | Change from Baseline to Week 24 in osteoid thickness. | ITT population, which included all randomized patients that received any treatment with asfotase alfa (2 mg/kg or 3 mg/kg thrice weekly), even if they discontinued or were lost to follow-up during the conduct of the clinical trial. Data imputation was not performed. | Posted | Mean | Standard Deviation | um | Baseline and Week 24 |
|
|
|
|
| Secondary | Change in Osteomalacia - Osteoid Volume/Bone Volume (as Measured by Trans-iliac Crest Bone Biopsy) | Change from Baseline to Week 24 in osteoid volume/bone volume (%), calculated as the absolute difference of the Baseline and Week 24 percentages. | ITT population, which included all randomized patients that received any treatment with asfotase alfa (2 mg/kg or 3 mg/kg thrice weekly), even if they discontinued or were lost to follow-up during the conduct of the clinical trial. Data imputation was not performed. | Posted | Mean | Standard Deviation | percentage points | Baseline and Week 24 |
|
|
|
|
| Secondary | Change in Osteomalacia - Mineralization Lag Time (as Measured by Trans-iliac Crest Bone Biopsy) | Change from Baseline to Week 24 in mineralization lag time. | ITT population, which included all randomized patients that received any treatment with asfotase alfa (2 mg/kg or 3 mg/kg thrice weekly), even if they discontinued or were lost to follow-up during the conduct of the clinical trial. Data imputation was not performed. | Posted | Mean | Standard Deviation | days | Baseline and Week 24 |
|
|
|
|
| Secondary | Change in Height (Z-scores) | Change from Baseline to Week 24 in Height Z-Score. Height Z-Scores assigned based on Centers for Disease Control (CDC) growth charts and methodology. | ITT population, which included all randomized patients that received any treatment with asfotase alfa (2 mg/kg or 3 mg/kg thrice weekly), even if they discontinued or were lost to follow-up during the conduct of the clinical trial. Data imputation was not performed. | Posted | Mean | Standard Deviation | Height Z score | Baseline and Week 24 |
|
|
|
|
| Secondary | Change in Biomarkers of Asfotase Alfa Activity as Measured by Plasma Inorganic Pyrophosphate (PPi) | Change from Baseline to Week 24 in Plasma PPi | ITT population, which included all randomized patients that received any treatment with asfotase alfa (2 mg/kg or 3 mg/kg thrice weekly), even if they discontinued or were lost to follow-up during the conduct of the clinical trial. Data imputation was not performed. | Posted | Mean | Standard Deviation | uM | Baseline and Week 24 |
|
|
|
|
| Secondary | Change in Biomarkers of Asfotase Alfa Activity as Measured by Pyridoxal-5'-Phosphate (PLP) | Change from Baseline to Week 24 in Plasma PLP | ITT population, which included all randomized patients that received any treatment with asfotase alfa (2 mg/kg or 3 mg/kg thrice weekly), even if they discontinued or were lost to follow-up during the conduct of the clinical trial. Data imputation was not performed. | Posted | Mean | Standard Deviation | ng/mL | Baseline and Week 24 |
|
|
|
|
| Secondary | Maximum Serum Concentration of Asfotase Alfa (Cmax). | Maximum serum concentration observed following single dose of asfotase alfa. | ITT population which included all randomized patients that received any treatment with asfotase alfa (2 mg/kg or 3 mg/kg thrice weekly). | Posted | Mean | Standard Deviation | U/L | Study Week 1 (0 to 48 hours post-dose) |
|
|
|
| Secondary | Time at Maximum Serum Concentration of Asfotase Alfa (Tmax) | Maximum serum concentration observed following single dose of asfotase alfa. | ITT population which included all randomized patients that received any treatment with asfotase alfa (2 mg/kg or 3 mg/kg thrice weekly). | Posted | Mean | Standard Deviation | hours | Study Week 1 (0 to 48 hours post-dose) |
|
|
|
| Secondary | Area Under Serum Concentration-time Curve to Last Measurable Concentration of Asfotase Alfa (AUCt) | Area under serum concentration-time curve to last measurable concentration following single dose of asfotase alfa. | ITT population which included all randomized patients that received any treatment with asfotase alfa (2 mg/kg or 3 mg/kg thrice weekly). | Posted | Mean | Standard Deviation | h*U/L | Study Week 1 (0 to 48 hours post-dose) |
|
|
|
| Secondary | Maximum Serum Concentration of Asfotase Alfa (Cmax). | Maximum serum concentration observed following multiple doses of asfotase alfa. | ITT population which included all randomized patients that received any treatment with asfotase alfa (2 mg/kg or 3 mg/kg thrice weekly). | Posted | Mean | Standard Deviation | U/L | Study Week 6 (0 to 48 hours post-dose) |
|
|
|
| Secondary | Time at Maximum Serum Concentration of Asfotase Alfa (Tmax). | Time at maximum serum concentration observed following multiple doses of asfotase alfa. | ITT population which included all randomized patients that received any treatment with asfotase alfa (2 mg/kg or 3 mg/kg thrice weekly). | Posted | Mean | Standard Deviation | hours | Study Week 6 (0 to 48 hours post-dose) |
|
|
|
| Secondary | Area Under Serum Concentration-time Curve to Last Measurable Concentration of Asfotase Alfa (AUCt) | Area under serum concentration-time curve to last measurable concentration following multiple doses of asfotase alfa. | ITT population which included all randomized patients that received any treatment with asfotase alfa (2 mg/kg or 3 mg/kg thrice weekly). | Posted | Mean | Standard Deviation | h*U/L | Study Week 6 (0 to 48 hours post-dose). |
|
|
|
| 0 |
| 6 |
| 6 |
| 6 |
| EG001 | Asfotase Alfa 3 mg/kg | 3 mg/kg administered thrice weekly as a subcutaneous (SC) injection | 0 | 7 | 7 | 7 |
| Injection site discoloration | General disorders | MedDRA 13.0 | Non-systematic Assessment |
|
| Injection site pruritis | General disorders | MedDRA 13.0 | Non-systematic Assessment |
|
| Injection site pain | General disorders | MedDRA 13.0 | Non-systematic Assessment |
|
| Injection site swelling | General disorders | MedDRA 13.0 | Non-systematic Assessment |
|
| Infusion site pain | General disorders | MedDRA 13.0 | Non-systematic Assessment |
|
| Procedural pain | Injury, poisoning and procedural complications | MedDRA 13.0 | Non-systematic Assessment |
|
| Excoriation | Injury, poisoning and procedural complications | MedDRA 13.0 | Non-systematic Assessment |
|
| Animal bite | Injury, poisoning and procedural complications | MedDRA 13.0 | Non-systematic Assessment |
|
| Procedural nausea | Injury, poisoning and procedural complications | MedDRA 13.0 | Non-systematic Assessment |
|
| Tongue injury | Injury, poisoning and procedural complications | MedDRA 13.0 | Non-systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA 13.0 | Non-systematic Assessment |
|
| Dental caries | Gastrointestinal disorders | MedDRA 13.0 | Non-systematic Assessment |
|
| Gastroesophageal reflux disease | Gastrointestinal disorders | MedDRA 13.0 | Non-systematic Assessment |
|
| Sensitivity of teeth | Gastrointestinal disorders | MedDRA 13.0 | Non-systematic Assessment |
|
| Teething | Gastrointestinal disorders | MedDRA 13.0 | Non-systematic Assessment |
|
| Toothache | Gastrointestinal disorders | MedDRA 13.0 | Non-systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA 13.0 | Non-systematic Assessment |
|
| Oropharyngeal pain | Respiratory, thoracic and mediastinal disorders | MedDRA 13.0 | Non-systematic Assessment |
|
| Nasal congestion | Respiratory, thoracic and mediastinal disorders | MedDRA 13.0 | Non-systematic Assessment |
|
| Rhinorrhea | Respiratory, thoracic and mediastinal disorders | MedDRA 13.0 | Non-systematic Assessment |
|
| Epistaxis | Respiratory, thoracic and mediastinal disorders | MedDRA 13.0 | Non-systematic Assessment |
|
| Rhinitis allergic | Respiratory, thoracic and mediastinal disorders | MedDRA 13.0 | Non-systematic Assessment |
|
| Upper respiratory tract infection | Infections and infestations | MedDRA 13.0 | Non-systematic Assessment |
|
| Otitis media | Infections and infestations | MedDRA 13.0 | Non-systematic Assessment |
|
| Sinusitis | Infections and infestations | MedDRA 13.0 | Non-systematic Assessment |
|
| Otitis externa | Infections and infestations | MedDRA 13.0 | Non-systematic Assessment |
|
| Pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA 13.0 | Non-systematic Assessment |
|
| Medial tibial stress syndrome | Musculoskeletal and connective tissue disorders | MedDRA 13.0 | Non-systematic Assessment |
|
| Unequal limb length | Musculoskeletal and connective tissue disorders | MedDRA 13.0 | Non-systematic Assessment |
|
| Seasonal allergy | Immune system disorders | MedDRA 13.0 | Non-systematic Assessment |
|
| Blood 1,25-dihydroxycholecaliferol decreased | Investigations | MedDRA 13.0 | Non-systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA 13.0 | Non-systematic Assessment |
|
| Scleral hemmorhage | Eye disorders | MedDRA 13.0 | Non-systematic Assessment |
|
| Dermatitis contact | Skin and subcutaneous tissue disorders | MedDRA 13.0 | Non-systematic Assessment |
|
| Eye Allergy | Eye disorders | MedDRA 13.0 | Non-systematic Assessment |
|
| Anal Fissure | Gastrointestinal disorders | MedDRA 13.0 | Non-systematic Assessment |
|
| Diarrhea | Gastrointestinal disorders | MedDRA 13.0 | Non-systematic Assessment |
|
| Tooth loss | Gastrointestinal disorders | MedDRA 13.0 | Non-systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA 13.0 | Non-systematic Assessment |
|
| Injection site hemorrhage | General disorders | MedDRA 13.0 | Non-systematic Assessment |
|
| Injection site nodule | General disorders | MedDRA 13.0 | Non-systematic Assessment |
|
| Irritability | General disorders | MedDRA 13.0 | Non-systematic Assessment |
|
| Edema peripheral | General disorders | MedDRA 13.0 | Non-systematic Assessment |
|
| Pain | General disorders | MedDRA 13.0 | Non-systematic Assessment |
|
| Hypersensitivity | Immune system disorders | MedDRA 13.0 | Non-systematic Assessment |
|
| Nasopharyngitis | Infections and infestations | MedDRA 13.0 | Non-systematic Assessment |
|
| Gastroenteritis viral | Infections and infestations | MedDRA 13.0 | Non-systematic Assessment |
|
| Blood 25-hydroxycholecalciferol decreased | Investigations | MedDRA 13.0 | Non-systematic Assessment |
|
| Vitamin B6 decreased | Investigations | MedDRA 13.0 | Non-systematic Assessment |
|
| Fall | Injury, poisoning and procedural complications | MedDRA 13.0 | Non-systematic Assessment |
|
| Limb Injury | Injury, poisoning and procedural complications | MedDRA 13.0 | Non-systematic Assessment |
|
| Foreign Body | Injury, poisoning and procedural complications | MedDRA 13.0 | Non-systematic Assessment |
|
| Laceration | Injury, poisoning and procedural complications | MedDRA 13.0 | Non-systematic Assessment |
|
| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA 13.0 | Non-systematic Assessment |
|
| Back Pain | Musculoskeletal and connective tissue disorders | MedDRA 13.0 | Non-systematic Assessment |
|
| Myalgia | Musculoskeletal and connective tissue disorders | MedDRA 13.0 | Non-systematic Assessment |
|
| Neck Pain | Musculoskeletal and connective tissue disorders | MedDRA 13.0 | Non-systematic Assessment |
|
| Sinus Congestion | Respiratory, thoracic and mediastinal disorders | MedDRA 13.0 | Non-systematic Assessment |
|
| Anxiety | Psychiatric disorders | MedDRA 13.0 | Non-systematic Assessment |
|
| Decreased appetite | Metabolism and nutrition disorders | MedDRA 13.0 | Non-systematic Assessment |
|
Not provided
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D009140 | Musculoskeletal Diseases |
| D001851 | Bone Diseases, Metabolic |
| D002128 | Calcium Metabolism Disorders |
| D014808 | Vitamin D Deficiency |
| D001361 | Avitaminosis |
| D003677 | Deficiency Diseases |
| D044342 | Malnutrition |
| D009748 | Nutrition Disorders |