Hyperbilirubinemia, Neonatal, Jaundice, Neonatal
Conditions
Keywords
G6PD deficiency, Antibody (ABO) incompatibility, Coombs positive ABO/ rhesus factor (RH) incompatibility, Intensive phototherapy in neonates
Brief summary
It is normal for red blood cells to die, even in newborn babies. The waste from that is called bilirubin. The liver clears bilirubin out of the body. Some babies are born with illness that makes red blood cells die too fast, so the liver is not strong enough to keep up with it. The yellowish color in eyes or skin means there is too much bilirubin in the body. It can be dangerous if a baby's bilirubin gets too high. Special lights are put on jaundiced babies (called phototherapy) to help the liver get rid of bilirubin. This study tests an experimental drug to see if it can help the liver even more, by safely cutting down the amount of bilirubin the body is making in the first place.
Detailed description
Participants randomized (1:1:1) to treatment groups will be term or near-term infants with isoimmune hemolytic disease or glucose-6-phosphate dehydrogenase (G6PD) deficiency.
Interventions
PROCEDUREPhototherapy
Phototherapy starts within 30 minutes before or after injection
DRUGStannsoporfin
Stannsoporfin (3.0 or 4.5 mg/kg) administered by intramuscular (IM) injection (a shot in the muscle)
DRUGPlacebo
Matching placebo administered by IM injection
Sponsors
InfaCare Pharmaceuticals Corporation, a Mallinckrodt Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
1 Hours to 72 Hours
Healthy volunteers
No
Inclusion criteria
1. Term and near term infants ≥35 and ≤ 43 weeks gestational age (GA), age 0-48 hours with antibody (ABO) or rhesus factor (Rh) incompatibility (anti C, c, D, E or e) who are Coombs positive, or age 0-72 hours with G6PD deficiency 2. Parental or guardian consent 3. Birth weight ≥ 2500 grams 4. At or above the age-specific threshold for initiating phototherapy (PT) per the American Academy of Pediatrics (AAP) guidelines based on measurement of total serum bilirubin (TSB) 5. Parents agree to observe light precautions for 10 days post treatment
Exclusion criteria
1. Elevated direct bilirubin ≥2 mg/dL, OR \> 20% of the total serum bilirubin 2. Alanine aminotransferase (ALT) \> 2 times the upper limit of normal (ULN) and/or aspartate aminotransferase (AST) \> 3 times ULN 3. Abnormal renal function defined as creatinine and/or blood urea nitrogen \>2 times the ULN 4. Any other clinically significant abnormalities on screening laboratory evaluation \[including electrocardiogram (ECG)\] that in the opinion of the investigator makes the patient unsuitable for the clinical trial 5. Apgar score ≤6 at age 5 minutes 6. An unexplained existing rash or skin erythema 7. Prior exposure to PT 8. Clinical suggestion of neonatal thyroid disease or current uncontrolled thyroid disease in the mother (maternal Hashimoto's disease is not exclusionary) 9. Cardio-respiratory distress, defined as a respiratory rate \>60 breaths per minute at time of enrollment 10. Any abnormal auditory or ophthalmologic findings on screening physical exam 11. Treatment or need for treatment in the neonate with medications that are photoreactive or may prolong the QT interval (erythromycin ointment for eye prophylaxis is permitted), or family history of Long QT syndrome 12. Known porphyrias or risk factors for porphyrias, including family history 13. A maternal history of systemic lupus erythematosus 14. Maternal use of phenobarbital 30 days before, or after delivery, if breast-feeding 15. Maternal current drug or alcohol abuse, or maternal history of drug or alcohol abuse that, in the opinion of the Investigator, would not make the patient a suitable candidate for participation in the clinical trial 16. Significant congenital anomalies or infections 17. Risk of requiring surgery or exposure to operating room (OR) lights in the first 2 weeks of life 18. Persistent hypoglycemia (blood glucose \<40 mg/dL) 19. Temperature instability defined as temperature consistently (3 consecutive times) \<36 degrees centigrade (ºC) and/or \>37.5 degrees centigrade (ºC) axillary 20. Use of intravenous immunoglobulin (IVIg) or albumin prior to study drug administration 21. Post-delivery treatment with medications that are known or suspected to displace bilirubin from albumin (e.g., ceftriaxone or sulfa-based antibiotics) 22. Use of photosensitizing drugs or agents 23. Unwillingness of parents/guardians to adhere to recommendations regarding light precautions 24. Exposure to any investigational medications or devices after delivery, or participation in another clinical trial while participating in this trial 25. Any other concurrent medical condition, which in the opinion of the Investigator, makes the patient unsuitable for the clinical trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total Serum Bilirubin (mg/dL) | Baseline, 48 hours post-treatment | Total serum bilirubin (TSB) was measured at baseline (the measure that qualified the baby for inclusion) and at 48 hours after treatment. If a baby was discharged before 48 hours, the last measurement before discharge was used \[last observation carried forward (LOCF)\]. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time (Hour) at Which TSB First Crosses at or Below the Defined Age-specific Threshold for 54-hours Post-treatment (PT) | within 54 hours | The hour that 50% of babies in the group (median) first crosses at or below the defined 54-hour threshold for the baby's age |
| Number of Participants With Phototherapy (PT) Failure | within 30 days after discharge | PT failure was defined by any of the following: * re-start of PT within 6 hours after stopping * re-hospitalization for hyperbilirubinaemia * use of intravenous immunoglobulin (IVIg) * need for an exchange transfusion |
| Number of Participants With Rebound Hyperbilirubinemia | within 54 hours | Rebound hyperbilirubinaemia was defined as an increase in TSB above the age-specific threshold for initiating phototherapy, following the discontinuation of the initial phototherapy. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 3.0 mg/kg Stannsoporfin Participants receive 3.0 mg/kg Stannsoporfin and phototherapy | 30 |
| 4.5 mg/kg Stannsoporfin Participants receive 4.5 mg/kg stannsoporfin and phototherapy | 31 |
| Placebo Participants receive placebo and phototherapy | 30 |
| Total | 91 |
Baseline characteristics
| Characteristic | Total | Placebo | 4.5 mg/kg Stannsoporfin | 3.0 mg/kg Stannsoporfin |
|---|---|---|---|---|
| Age at Qualifying TSB Greater than 12 h to Less than or equal to 24 h | 26 Participants | 7 Participants | 8 Participants | 11 Participants |
| Age at Qualifying TSB Greater than 24 h to Less than or equal to 32 h | 17 Participants | 7 Participants | 7 Participants | 3 Participants |
| Age at Qualifying TSB Greater than 32 h to Less than or equal to 40 h | 6 Participants | 3 Participants | 2 Participants | 1 Participants |
| Age at Qualifying TSB Greater than 40 h | 7 Participants | 3 Participants | 2 Participants | 2 Participants |
| Age at Qualifying TSB Less than or equal to 12 h | 35 Participants | 10 Participants | 12 Participants | 13 Participants |
| Age, Continuous | 23.88 Hour STANDARD_DEVIATION 11.608 | 25.92 Hour STANDARD_DEVIATION 12.361 | 24.05 Hour STANDARD_DEVIATION 11.02 | 21.66 Hour STANDARD_DEVIATION 11.417 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 31 Participants | 15 Participants | 9 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 60 Participants | 15 Participants | 22 Participants | 23 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 38 Participants | 9 Participants | 13 Participants | 16 Participants |
| Race (NIH/OMB) More than one race | 17 Participants | 8 Participants | 5 Participants | 4 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 34 Participants | 12 Participants | 13 Participants | 9 Participants |
| Sex: Female, Male Female | 43 Participants | 13 Participants | 15 Participants | 15 Participants |
| Sex: Female, Male Male | 48 Participants | 17 Participants | 16 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 30 | 0 / 31 | 0 / 30 |
| other Total, other adverse events | 28 / 30 | 21 / 31 | 22 / 30 |
| serious Total, serious adverse events | 5 / 30 | 4 / 31 | 6 / 30 |
Outcome results
Primary
Total Serum Bilirubin (mg/dL)
Total serum bilirubin (TSB) was measured at baseline (the measure that qualified the baby for inclusion) and at 48 hours after treatment. If a baby was discharged before 48 hours, the last measurement before discharge was used \[last observation carried forward (LOCF)\].
Time frame: Baseline, 48 hours post-treatment
Population: Intention to treat (ITT) analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 3.0 mg/kg Stannsoporfin | Total Serum Bilirubin (mg/dL) | Baseline | 9.82 mg/dL | Standard Deviation 2.641 |
| 3.0 mg/kg Stannsoporfin | Total Serum Bilirubin (mg/dL) | 48 hours post-treatment | 8.48 mg/dL | Standard Deviation 1.973 |
| 4.5 mg/kg Stannsoporfin | Total Serum Bilirubin (mg/dL) | Baseline | 9.97 mg/dL | Standard Deviation 2.967 |
| 4.5 mg/kg Stannsoporfin | Total Serum Bilirubin (mg/dL) | 48 hours post-treatment | 8.86 mg/dL | Standard Deviation 2.142 |
| Placebo | Total Serum Bilirubin (mg/dL) | Baseline | 9.92 mg/dL | Standard Deviation 2.211 |
| Placebo | Total Serum Bilirubin (mg/dL) | 48 hours post-treatment | 11.67 mg/dL | Standard Deviation 2.337 |
p-value: =0.000002195% CI: [-44, -19.283]LS Mean Difference vs Placebo
p-value: =0.00002695% CI: [-39.657, -15.142]LS Mean Difference vs Placebo
Secondary
Number of Participants With Phototherapy (PT) Failure
PT failure was defined by any of the following: * re-start of PT within 6 hours after stopping * re-hospitalization for hyperbilirubinaemia * use of intravenous immunoglobulin (IVIg) * need for an exchange transfusion
Time frame: within 30 days after discharge
Population: Intention to treat
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 3.0 mg/kg Stannsoporfin | Number of Participants With Phototherapy (PT) Failure | PT failure Occurred | 3 Participants |
| 3.0 mg/kg Stannsoporfin | Number of Participants With Phototherapy (PT) Failure | Did not occur | 27 Participants |
| 4.5 mg/kg Stannsoporfin | Number of Participants With Phototherapy (PT) Failure | PT failure Occurred | 1 Participants |
| 4.5 mg/kg Stannsoporfin | Number of Participants With Phototherapy (PT) Failure | Did not occur | 30 Participants |
| Placebo | Number of Participants With Phototherapy (PT) Failure | PT failure Occurred | 8 Participants |
| Placebo | Number of Participants With Phototherapy (PT) Failure | Did not occur | 22 Participants |
Secondary
Number of Participants With Rebound Hyperbilirubinemia
Rebound hyperbilirubinaemia was defined as an increase in TSB above the age-specific threshold for initiating phototherapy, following the discontinuation of the initial phototherapy.
Time frame: within 54 hours
Population: Intention to treat
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 3.0 mg/kg Stannsoporfin | Number of Participants With Rebound Hyperbilirubinemia | Occurred | 0 Participants |
| 3.0 mg/kg Stannsoporfin | Number of Participants With Rebound Hyperbilirubinemia | Did not occur | 30 Participants |
| 4.5 mg/kg Stannsoporfin | Number of Participants With Rebound Hyperbilirubinemia | Occurred | 1 Participants |
| 4.5 mg/kg Stannsoporfin | Number of Participants With Rebound Hyperbilirubinemia | Did not occur | 30 Participants |
| Placebo | Number of Participants With Rebound Hyperbilirubinemia | Occurred | 3 Participants |
| Placebo | Number of Participants With Rebound Hyperbilirubinemia | Did not occur | 27 Participants |
Secondary
Time (Hour) at Which TSB First Crosses at or Below the Defined Age-specific Threshold for 54-hours Post-treatment (PT)
The hour that 50% of babies in the group (median) first crosses at or below the defined 54-hour threshold for the baby's age
Time frame: within 54 hours
Population: ITT Analysis Set minus 2 participants who received placebo and did not reach the defined threshold for their age within 54 hours
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 3.0 mg/kg Stannsoporfin | Time (Hour) at Which TSB First Crosses at or Below the Defined Age-specific Threshold for 54-hours Post-treatment (PT) | 11.8 hours |
| 4.5 mg/kg Stannsoporfin | Time (Hour) at Which TSB First Crosses at or Below the Defined Age-specific Threshold for 54-hours Post-treatment (PT) | 10.6 hours |
| Placebo | Time (Hour) at Which TSB First Crosses at or Below the Defined Age-specific Threshold for 54-hours Post-treatment (PT) | 20.9 hours |