Trial Outcomes & Findings for Safety and Efficacy Study of Asfotase Alfa in Severely Affected Infants With Hypophosphatasia (HPP) (NCT NCT00744042)
NCT ID: NCT00744042
Last Updated: 2019-04-01
Results Overview
A 7-point RGI-C (Radiographic Global Impression of Change) score was used to rate change in rickets severity. Scores ranged from -3 (severe worsening of rickets) to +3 (complete healing of rickets). 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. Average scores were derived for each patient at each assessment.
Recruitment status
COMPLETED
Study phase
PHASE1/PHASE2
Target enrollment
11 participants
Primary outcome timeframe
24 weeks
Results posted on
2019-04-01
Participant Flow
The trial was posted on clinicaltrials.gov. Physicians managing the care of infants and young children with a confirmed diagnosis of HPP contacted existing sites or requested assistance with site set up from the sponsor.
All screened patients met eligibility criteria and were enrolled in the study.
Participant milestones
| Measure |
Asfotase Alfa
All patients received an initial single intravenous (IV) infusion of 2 mg/kg asfotase alfa for the first week followed by regular administration of subcutaneous (SC) injections of 1 mg/kg asfotase alfa 3 times/week (total 3 mg/kg/week).
|
|---|---|
|
Overall Study
STARTED
|
11
|
|
Overall Study
COMPLETED
|
10
|
|
Overall Study
NOT COMPLETED
|
1
|
Reasons for withdrawal
| Measure |
Asfotase Alfa
All patients received an initial single intravenous (IV) infusion of 2 mg/kg asfotase alfa for the first week followed by regular administration of subcutaneous (SC) injections of 1 mg/kg asfotase alfa 3 times/week (total 3 mg/kg/week).
|
|---|---|
|
Overall Study
Withdrawal by Subject
|
1
|
Baseline Characteristics
Safety and Efficacy Study of Asfotase Alfa in Severely Affected Infants With Hypophosphatasia (HPP)
Baseline characteristics by cohort
| Measure |
Asfotase Alfa
n=11 Participants
All enrolled patients receive a single IV (intravenous) dose of Asfotase Alfa of 2 mg/kg followed by 7 days of observation. Following an assessment of safety data by an independent Data Safety Monitoring Board (DSMB), patients begin thrice weekly SC (subcutaneous) injections of Asfotase Alfa at a dose of 1 mg/kg for the remaining 23 weeks of the study.
|
|---|---|
|
Age, Categorical
<=18 years
|
11 Participants
n=99 Participants
|
|
Age, Categorical
Between 18 and 65 years
|
0 Participants
n=99 Participants
|
|
Age, Categorical
>=65 years
|
0 Participants
n=99 Participants
|
|
Age, Continuous
|
1.11 years
STANDARD_DEVIATION 1.13 • n=99 Participants
|
|
Sex: Female, Male
Female
|
7 Participants
n=99 Participants
|
|
Sex: Female, Male
Male
|
4 Participants
n=99 Participants
|
|
Region of Enrollment
Canada
|
1 participants
n=99 Participants
|
|
Region of Enrollment
United States
|
7 participants
n=99 Participants
|
|
Region of Enrollment
United Arab Emirates
|
1 participants
n=99 Participants
|
|
Region of Enrollment
United Kingdom
|
2 participants
n=99 Participants
|
PRIMARY outcome
Timeframe: 24 weeksPopulation: ITT (intention to treat)
A 7-point RGI-C (Radiographic Global Impression of Change) score was used to rate change in rickets severity. Scores ranged from -3 (severe worsening of rickets) to +3 (complete healing of rickets). 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. Average scores were derived for each patient at each assessment.
Outcome measures
| Measure |
Study Week 3 Subcutaneous Dose (1mg/kg 3x/Week)
Participants received subcutaneous (SC) asfotase alfa starting on Day 8 (Week 2) (1 mg/kg 3x/week). PK samples drawn predose to 48 hours post-dose for PK analysis following multiple SC doses.
|
Asfotase Alfa
n=11 Participants
All HPP affected infants will receive a single IV (intravenous) dose of Asfotase Alfa of 2 mg/kg followed by 7 days of observation. Following an assessment of safety data by an independent Data Safety Monitoring Board (DSMB), patients will then begin every other day SC (subcutaneous) injections of Asfotase Alfa at a dose of 1 mg/kg for 23 weeks. End of Study will be at 24 weeks.
|
Study Week 2 Subcutaneous Dose (1 mg/kg 3x/Week)
Participants received subcutaneous (SC) asfotase alfa starting on Day 8 (Week 2) (1 mg/kg 3x/week). PK samples drawn predose to 48 hours post-dose for PK analysis following single SC dose.
|
|---|---|---|---|
|
Change in Rickets Severity From Baseline to Week 24, Based on Assessment of Skeletal Radiographs Using Radiologic Global Impression of Change (RGI-C)
|
—
|
2.00 Units on a scale
Interval 0.0 to 2.33
|
—
|
SECONDARY outcome
Timeframe: Study Week 1 (0 to 168 hours post-dose). Study Week 2 and Study Week 3 (0 to 48 hours post-dose)Population: ITT population. N=number of patients who received a full dose of asfotase alfa and had sufficient data for non-compartmental analysis.
Maximum serum concentration observed during intensive PK sampling interval.
Outcome measures
| Measure |
Study Week 3 Subcutaneous Dose (1mg/kg 3x/Week)
n=7 Participants
Participants received subcutaneous (SC) asfotase alfa starting on Day 8 (Week 2) (1 mg/kg 3x/week). PK samples drawn predose to 48 hours post-dose for PK analysis following multiple SC doses.
|
Asfotase Alfa
n=6 Participants
All HPP affected infants will receive a single IV (intravenous) dose of Asfotase Alfa of 2 mg/kg followed by 7 days of observation. Following an assessment of safety data by an independent Data Safety Monitoring Board (DSMB), patients will then begin every other day SC (subcutaneous) injections of Asfotase Alfa at a dose of 1 mg/kg for 23 weeks. End of Study will be at 24 weeks.
|
Study Week 2 Subcutaneous Dose (1 mg/kg 3x/Week)
n=7 Participants
Participants received subcutaneous (SC) asfotase alfa starting on Day 8 (Week 2) (1 mg/kg 3x/week). PK samples drawn predose to 48 hours post-dose for PK analysis following single SC dose.
|
|---|---|---|---|
|
Maximum Serum Concentration of Asfotase Alfa (Cmax)
|
897 U/L
Standard Deviation 491
|
2230 U/L
Standard Deviation 1100
|
376 U/L
Standard Deviation 226
|
SECONDARY outcome
Timeframe: Study Week 1 (0 to 168 hours post-dose). Study Week 2 and Study Week 3 (0 to 48 hours post-dose).Population: ITT population. N=number of patients who received a full dose of asfotase alfa and had sufficient data for non-compartmental analysis.
Time at maximum serum concentration observed during intensive PK sampling interval.
Outcome measures
| Measure |
Study Week 3 Subcutaneous Dose (1mg/kg 3x/Week)
n=7 Participants
Participants received subcutaneous (SC) asfotase alfa starting on Day 8 (Week 2) (1 mg/kg 3x/week). PK samples drawn predose to 48 hours post-dose for PK analysis following multiple SC doses.
|
Asfotase Alfa
n=6 Participants
All HPP affected infants will receive a single IV (intravenous) dose of Asfotase Alfa of 2 mg/kg followed by 7 days of observation. Following an assessment of safety data by an independent Data Safety Monitoring Board (DSMB), patients will then begin every other day SC (subcutaneous) injections of Asfotase Alfa at a dose of 1 mg/kg for 23 weeks. End of Study will be at 24 weeks.
|
Study Week 2 Subcutaneous Dose (1 mg/kg 3x/Week)
n=7 Participants
Participants received subcutaneous (SC) asfotase alfa starting on Day 8 (Week 2) (1 mg/kg 3x/week). PK samples drawn predose to 48 hours post-dose for PK analysis following single SC dose.
|
|---|---|---|---|
|
Time at Maximum Serum Concentration of Asfotase Alfa (Tmax)
|
12.0 hour
Standard Deviation 7.7
|
4.3 hour
Standard Deviation 4.3
|
29.7 hour
Standard Deviation 13.2
|
SECONDARY outcome
Timeframe: Study Week 1 (0 to 168 hours post-dose). Study Week 2 and Study Week 3 (0 to 48 hours post-dose).Population: ITT population. N=number of patients who received a full dose of asfotase alfa and had sufficient data for non-compartmental analysis.
Area under serum concentration-time curve to last measurable concentration during intensive PK sampling interval.
Outcome measures
| Measure |
Study Week 3 Subcutaneous Dose (1mg/kg 3x/Week)
n=7 Participants
Participants received subcutaneous (SC) asfotase alfa starting on Day 8 (Week 2) (1 mg/kg 3x/week). PK samples drawn predose to 48 hours post-dose for PK analysis following multiple SC doses.
|
Asfotase Alfa
n=6 Participants
All HPP affected infants will receive a single IV (intravenous) dose of Asfotase Alfa of 2 mg/kg followed by 7 days of observation. Following an assessment of safety data by an independent Data Safety Monitoring Board (DSMB), patients will then begin every other day SC (subcutaneous) injections of Asfotase Alfa at a dose of 1 mg/kg for 23 weeks. End of Study will be at 24 weeks.
|
Study Week 2 Subcutaneous Dose (1 mg/kg 3x/Week)
n=7 Participants
Participants received subcutaneous (SC) asfotase alfa starting on Day 8 (Week 2) (1 mg/kg 3x/week). PK samples drawn predose to 48 hours post-dose for PK analysis following single SC dose.
|
|---|---|---|---|
|
Area Under Serum Concentration-time Curve to Last Measurable Concentration of Asfotase Alfa (AUCt)
|
33700 h*U/L
Standard Deviation 19700
|
79800 h*U/L
Standard Deviation 21700
|
14700 h*U/L
Standard Deviation 9730
|
Adverse Events
Asfotase Alfa
Serious events: 7 serious events
Other events: 11 other events
Deaths: 0 deaths
Serious adverse events
| Measure |
Asfotase Alfa
n=11 participants at risk
All patients who received any asfotase alfa treatment, regardless of whether they were lost to follow-up or dropped out of the trial.
|
|---|---|
|
Infections and infestations
H1N1 Influenza
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Infections and infestations
Pneumonia
|
18.2%
2/11 • Number of events 3 • 6 months
|
|
Infections and infestations
Gastroenteritis salmonella
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Infections and infestations
Lower respiratory tract infection viral
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Infections and infestations
Pneumonia respiratory syncytial viral
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Infections and infestations
Respiratory syncytial virus bronchiolitis
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Infections and infestations
Sepsis
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Respiratory, thoracic and mediastinal disorders
Respiratory distress
|
18.2%
2/11 • Number of events 4 • 6 months
|
|
Respiratory, thoracic and mediastinal disorders
Respiratory failure
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Respiratory, thoracic and mediastinal disorders
Respiratory depression
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Respiratory, thoracic and mediastinal disorders
Hypoxia
|
18.2%
2/11 • Number of events 2 • 6 months
|
|
Respiratory, thoracic and mediastinal disorders
Obstructive airways disorder
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Respiratory, thoracic and mediastinal disorders
Restrictive pulmonary disease
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Nervous system disorders
Convulsion
|
18.2%
2/11 • Number of events 2 • 6 months
|
|
Nervous system disorders
Intracranial pressure increased
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Investigations
Oxygen saturation decreased
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Congenital, familial and genetic disorders
Craniosynostosis
|
27.3%
3/11 • Number of events 3 • 6 months
|
|
Injury, poisoning and procedural complications
Collapse of lung
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Infections and infestations
Upper respiratory tract infection
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Infections and infestations
Lower respiratory tract infection
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
General disorders
Medical device complication
|
9.1%
1/11 • Number of events 1 • 6 months
|
Other adverse events
| Measure |
Asfotase Alfa
n=11 participants at risk
All patients who received any asfotase alfa treatment, regardless of whether they were lost to follow-up or dropped out of the trial.
|
|---|---|
|
General disorders
Pyrexia
|
45.5%
5/11 • Number of events 5 • 6 months
|
|
General disorders
Irritability
|
36.4%
4/11 • Number of events 4 • 6 months
|
|
General disorders
Injection site erythema
|
18.2%
2/11 • Number of events 15 • 6 months
|
|
General disorders
Catheter site erythema
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
General disorders
Catheter site rash
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
General disorders
Thrombosis in device
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
General disorders
Chills
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
General disorders
Drug withdrawal syndrome
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
General disorders
Hernia
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
General disorders
Hypothermia
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
General disorders
Injection site hematoma
|
9.1%
1/11 • Number of events 4 • 6 months
|
|
General disorders
Injection site induration
|
9.1%
1/11 • Number of events 2 • 6 months
|
|
General disorders
Injection site nodule
|
9.1%
1/11 • Number of events 2 • 6 months
|
|
General disorders
Injection site pain
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
General disorders
Injection site papule
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
General disorders
Injection site pruritis
|
9.1%
1/11 • Number of events 2 • 6 months
|
|
General disorders
Injection site rash
|
9.1%
1/11 • Number of events 2 • 6 months
|
|
General disorders
Injection site warmth
|
9.1%
1/11 • Number of events 2 • 6 months
|
|
General disorders
Edema
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Infections and infestations
Pneumonia
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Infections and infestations
Nasopharyngitis
|
18.2%
2/11 • Number of events 4 • 6 months
|
|
Infections and infestations
Otitis media
|
18.2%
2/11 • Number of events 2 • 6 months
|
|
Infections and infestations
Sinusitis
|
18.2%
2/11 • Number of events 3 • 6 months
|
|
Infections and infestations
Upper respiratory tract infection
|
18.2%
2/11 • Number of events 4 • 6 months
|
|
Infections and infestations
Bacterial tracheitis
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Infections and infestations
Bronchiolitis
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Infections and infestations
Device related infection
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Infections and infestations
Exanthema subitum
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Infections and infestations
Gastroenteritis
|
9.1%
1/11 • Number of events 2 • 6 months
|
|
Infections and infestations
Gastroenteritis rotavirus
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Infections and infestations
Pneumonia staphylococcal
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Infections and infestations
Skin candida
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Infections and infestations
Tracheitis
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Infections and infestations
Viral infection
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Infections and infestations
Pneumonia respiratory syncytial viral
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Gastrointestinal disorders
Vomiting
|
27.3%
3/11 • Number of events 3 • 6 months
|
|
Gastrointestinal disorders
Constipation
|
36.4%
4/11 • Number of events 4 • 6 months
|
|
Gastrointestinal disorders
Flatulence
|
18.2%
2/11 • Number of events 2 • 6 months
|
|
Gastrointestinal disorders
Gastroesophageal reflux disease
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Gastrointestinal disorders
Gingival erythema
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Gastrointestinal disorders
Gastritis
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Gastrointestinal disorders
Nausea
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Gastrointestinal disorders
Stomatitis
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Gastrointestinal disorders
Teething
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Investigations
Hemoglobin decreased
|
36.4%
4/11 • Number of events 9 • 6 months
|
|
Investigations
Urine calcium/creatinine ratio increased
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Respiratory, thoracic and mediastinal disorders
Cough
|
9.1%
1/11 • Number of events 2 • 6 months
|
|
Respiratory, thoracic and mediastinal disorders
Nasal ulcer
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Respiratory, thoracic and mediastinal disorders
Tachypnea
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Injury, poisoning and procedural complications
Fall
|
18.2%
2/11 • Number of events 2 • 6 months
|
|
Injury, poisoning and procedural complications
Procedural pain
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Injury, poisoning and procedural complications
Procedural site reaction
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Injury, poisoning and procedural complications
Radius fracture
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Injury, poisoning and procedural complications
Wound
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Musculoskeletal and connective tissue disorders
Bone pain
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Musculoskeletal and connective tissue disorders
Myalgia
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Musculoskeletal and connective tissue disorders
Pain in extremity
|
9.1%
1/11 • Number of events 2 • 6 months
|
|
Cardiac disorders
Bradycardia
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Metabolism and nutrition disorders
Hypocalcemia
|
18.2%
2/11 • Number of events 2 • 6 months
|
|
Metabolism and nutrition disorders
Food intolerance
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Metabolism and nutrition disorders
Hypercalcemia
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Metabolism and nutrition disorders
Hyperphosphatemia
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Nervous system disorders
Headache
|
9.1%
1/11 • Number of events 2 • 6 months
|
|
Psychiatric disorders
Drug dependence
|
27.3%
3/11 • Number of events 3 • 6 months
|
|
Psychiatric disorders
Agitation
|
18.2%
2/11 • Number of events 2 • 6 months
|
|
Psychiatric disorders
Breath holding
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Congenital, familial and genetic disorders
Congenital bowing of long bones
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Skin and subcutaneous tissue disorders
Dermatitis diaper
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Skin and subcutaneous tissue disorders
Erythema
|
9.1%
1/11 • Number of events 2 • 6 months
|
|
Skin and subcutaneous tissue disorders
Excessive granulation tissue
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Skin and subcutaneous tissue disorders
Hyperhidrosis
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Skin and subcutaneous tissue disorders
Increased tendency to bruise
|
9.1%
1/11 • Number of events 6 • 6 months
|
|
Skin and subcutaneous tissue disorders
Piloerection
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Renal and urinary disorders
Nephrolithiasis
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Blood and lymphatic system disorders
Anemia
|
18.2%
2/11 • Number of events 2 • 6 months
|
|
Eye disorders
Ocular hyperaemia
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Surgical and medical procedures
Central venous catheter removal
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Vascular disorders
Flushing
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Congenital, familial and genetic disorders
Craniosynostosis
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Congenital, familial and genetic disorders
Atrial septal defect
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
General disorders
Pain
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Injury, poisoning and procedural complications
Feeding tube complication
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Investigations
Culture positive
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Psychiatric disorders
Anxiety
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Respiratory, thoracic and mediastinal disorders
Pharyngeal erythema
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Respiratory, thoracic and mediastinal disorders
Respiratory depression
|
9.1%
1/11 • Number of events 2 • 6 months
|
|
Metabolism and nutrition disorders
Metabolis acidosis
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Vascular disorders
Hypertension
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Vascular disorders
Secondary hypertension
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Cardiac disorders
Tachycardia
|
18.2%
2/11 • Number of events 2 • 6 months
|
|
Gastrointestinal disorders
Diarrhea
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Skin and subcutaneous tissue disorders
Pruritus
|
9.1%
1/11 • Number of events 1 • 6 months
|
|
Immune system disorders
Seasonal allergy
|
9.1%
1/11 • Number of events 1 • 6 months
|
Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place
Restriction type: LTE60