Synergistic Pharmacologic Intervention for Prevention of ROP (SPIPROP Study)
Study Details
Study Description
Brief Summary
Phase 2, open-label, randomized, multi-center studies in infants and premature infants are necessary to determine treatment and preventative strategies for ROP. This study was designed to: a) target infants at the highest risk of ROP in a large number of centers with variable rates of ROP (all stages and severe ROP or stage 3+); and b) assess whether caffeine plus systemic or ophthalmic NSAID will decrease ROP among infants most at risk for ROP. The study is designed to determine whether the novel treatment regimens are safe and potentially effective for ROP prevention and to obtain requisite data for the development of a Phase III efficacy/safety randomized blinded trial. Since caffeine is used extensively in NICUs as standard of care for ELGANs, no placebo group is included.
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
|
Phase 2 |
Detailed Description
This study will evaluate the safety, tolerability and PK-PD of, and to compare and contrast, IV Ibuprofen with Caffeine and Ketorolac eye drops with Caffeine in ELGAN infants <28 weeks GA for 14 days duration to treat and preferably prevent ROP associated with prematurity and
ELGAN. The specific aims of this trial are:
Aim 1: To establish the synergistic effect of local ophthalmic NSIADs and systemic caffeine as optimal therapies for the attenuation and/or prevention of severe ROP. Hypothesis: Ocular Ketorolac or systemic Ibuprofen potentiated with systemic Caffeine will prevent or diminish the severity of ROP. We will: a) Evaluate the safety, tolerability, and efficacy of early postnatal local ophthalmic NSIADs for prevention of severe ROP in ELGANs. b) Determine the pharmacokinetics, pharmacodymanics and pharmacogenomics of NSAIDs potentiated with caffeine for prevention of ROP.
Aim 2: To identify a "critical" number of arterial oxygen desaturations as a key risk factor for severe ROP.
Hypothesis: A "critical" number of daily arterial oxygen desaturations during the first two weeks of life is a key risk factor for severe ROP. We will: a) Further define the role of VEGF, IGF, MMPs, and ROS in ROP and correlate the levels with the number of arterial oxygen desaturations. b) Establish and identify whether increased serum VEGF in infants with severe ROP is the diffusible isoform VEGF121. This isoform is formed from VEGF proteolysis by plasmin and MMPs. MMPs also cleave Notch/Dll4, which acts as a regulator of VEGF signaling.
Aim 3: To determine whether infants at risk for severe ROP are haploinsufficient for the delta-like ligand 4 (Dll4).
Hypothesis: ELGANs at risk for severe ROP will have different pattern of gene expression specifically related to the Notch signaling pathway, as has been previously shown in animal models. We will: a) Examine cord blood, cord tissue, and placental tissue to compare the gene profile of VEGF and Notch signaling pathways among infants who develop severe ROP and those who do not; and b) Determine whether NSAIDs and/or Caffeine will confer protective benefits on Notch/Dll4 signaling and prevent the development of severe ROP.
This is a phase 2b, randomized, open label, multi-center, safety, tolerability and efficacy study comparing 3 interventions for possible prevention of ROP. The trial will be conducted in at least 8 investigational sites including the Neonatal networks (SUNY Downstate and the Brooklyn-Queens Neonatal Network sites, SUNY Stony Brook), and Miller Children's Hospital, Long Beach, CA. An independent DSMB will assess safety during the study. This study will monitor for safety while on study drug and for 7 days after last dose of drug. An exploratory study to determine the role of pharmacodynamic, drug concentrations (as surrogate of PK profile) and pharmacogenomics will also be conducted in this patient population.
One hundred and twenty preterm infants (<28 weeks gestation; <1250 grams) between 0 and 72 hours of life will be randomized to receive either:
-
Caffeine citrate IV (20 mg/kg loading dose followed by 5 mg/kg/day maintenance dose) plus placebo saline IV (1 ml/kg followed by 0.25 ml/kg) for 5 days plus sterile normal saline (one drop two times a day) for 14 days (n=40);
-
Caffeine citrate as described in group 1 plus Ibuprofen (10 mg/kg loading dose followed by low dose ibuprofen 2.5 mg/kg/day) for 5 days plus sterile normal saline (one drop two times a day) for 14 days (n=40); and
-
Caffeine citrate plus saline IV placebo as described in group 1, and Ketorolac (Acuvail) eye drops (one drop two times a day) for 14 days (n=40)
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Active Comparator: Caffeine+Saline IV+Saline drops Caffeine citrate IV (20 mg/kg loading dose, 5 mg/kg/day maintenance dose) plus placebo saline IV (1 ml/kg followed by 0.25 ml/kg) for 5 days plus sterile normal saline (one drop two times a day) for 14 days (n=40); Caffeine is the intervention |
Drug: Caffeine citrate
Caffeine citrate IV (20 mg/kg loading dose, 5 mg/kg/day maintenance dose)
Other Names:
|
Experimental: Caffeine+Ibp IV+Saline drops Caffeine citrate as described in group 1, plus Ibuprofen (10 mg/kg loading dose followed by low dose ibuprofen 2.5 mg/kg/day) for 5 days plus sterile normal saline (one drop two times a day) for 14 days (n=40); Ibuprofen is the intervention |
Drug: Ibuprofen
Ibuprofen (10 mg/kg loading dose followed by low dose ibuprofen 2.5 mg/kg/day) for 5 days
Other Names:
|
Experimental: Caffeine+Saline+Ketorolac drops Caffeine citrate plus saline IV placebo as described in group 1, and Ketorolac (Acuvail) eye drops (one drop two times a day) for 14 days (n=40); Ketorolac is the intervention |
Drug: Ketorolac
Ketorolac (Acuvail) eye drops (one drop two times a day) for 14 days
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Efficacy as Measured by the Number of Participants Presenting With Retinopathy of Prematurity (ROP) and the Rate of Stages/Grade of ROP. [50 weeks PCA +/- 7 days]
ROP (all grades) will be graded using International ROP Classification and severe ROP (Stage 3+ disease) or need for laser or Avastin The rate of mild (stage 1), moderate (stage 2) and severe ROP (stages >3) will be calculated as the number of infants diagnosed with ROP over the number of infants receiving retinal examinations. The study enrolled only 14 of the projected sample of 120, and the low enrollment did not allow meaningful analyses of efficacy and safety.
Secondary Outcome Measures
- Number of Participants With Adverse Events as a Measure of Safety and Tolerability [Eye examinations was done at standard of care through discharge and once, at 50 weeks PCA. All infants underwent routine eye examination by a pediatric ophthalmologist according to the International Classification for ROP]
We did not reach the target number of participants needed to measure statistically reliable outcome measure. The secondary outcome measure included Intraventricular hemorrhage (Papile's criteria) and ocular examination for corneal lesions.
Eligibility Criteria
Criteria
Inclusion Criteria:
- Neonates at high risk for ROP as outlined by the American Academy of Pediatrics, Section on Ophthalmology; American Association for Pediatric Ophthalmology and Strabismus; and American Academy of Ophthalmology (129) will be enrolled. Inclusion criteria are:
-
all infants with a birth weight of less than 1250 grams;
-
all infants with a gestational age of 28 weeks or less; and
-
all infants who required oxygen therapy and ventilator support within the first 2 days of life.
Exclusion Criteria:
- Exclusion criteria are:
-
major congenital malformations and or chromosomal anomalies including duct-dependent cardiac anomalies;
-
maternal antenatal NSAID exposure <72 hours before birth;
-
renal failure or oliguria defined as a urine flow rate <0.5 mL/kg/hour in the 8 hours prior to randomization. Anuria is acceptable if infant is less than 24 hours of life;
-
platelet count <75,000.mm3;
-
clinical bleeding such as oozing from puncture sites; and
-
participation in other clinical drug trials while subject participates in this study and for 7 days after last dose of study drug.
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | SUNY Downstate Medical Center/University Hospital of Brooklyn | Brooklyn | New York | United States | 11203 |
Sponsors and Collaborators
- State University of New York - Downstate Medical Center
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
- Food and Drug Administration (FDA)
Investigators
- Principal Investigator: Jacob V Aranda, MD, PhD, SUNY Downstate Medical Center, University Hospital of Brooklyn
Study Documents (Full-Text)
More Information
Publications
None provided.- 349622
- 1U54HD071594
Study Results
Participant Flow
Recruitment Details | The study started on Jan 01, 2015, and ended on Jun 30, 2018. Ninety-Eight (98) participants have been screened at five study sites. However, only 14 participants were enrolled. The reasons for poor enrollment were mostly due to refusal to participate, and some did not meet the eligibility criteria. All participants completed the study. |
---|---|
Pre-assignment Detail | The study screened 98 subjects when most mothers were admitted for preterm labor. They were treated successfully with tocolysis and other clinical managements (e.g. bed rest, magnesium sulfate etc.) which resulted in prolonging the pregnancy beyond 28 weeks at which time they met exclusion criteria and no longer eligible for the study.. |
Arm/Group Title | Caffeine+Saline IV+Saline Drops | Caffeine+Ibp IV+Saline Drops | Caffeine+Saline+Ketorolac Drops |
---|---|---|---|
Arm/Group Description | Caffeine citrate IV (20 mg/kg loading dose, 5 mg/kg/day maintenance dose) plus placebo saline IV (1 ml/kg followed by 0.25 ml/kg) for 5 days plus sterile normal saline (one drop two times a day) for 14 days (n=40); Caffeine is the intervention Caffeine citrate: Caffeine citrate IV (20 mg/kg loading dose, 5 mg/kg/day maintenance dose) | Caffeine citrate as described in group 1, plus Ibuprofen (10 mg/kg loading dose followed by low dose ibuprofen 2.5 mg/kg/day) for 5 days plus sterile normal saline (one drop two times a day) for 14 days (n=40); Ibuprofen is the intervention Ibuprofen: Ibuprofen (10 mg/kg loading dose followed by low dose ibuprofen 2.5 mg/kg/day) for 5 days | Caffeine citrate plus saline IV placebo as described in group 1, and Ketorolac (Acuvail) eye drops (one drop two times a day) for 14 days (n=40); Ketorolac is the intervention Ketorolac: Ketorolac (Acuvail) eye drops (one drop two times a day) for 14 days |
Period Title: Overall Study | |||
STARTED | 6 | 3 | 5 |
COMPLETED | 6 | 3 | 5 |
NOT COMPLETED | 0 | 0 | 0 |
Baseline Characteristics
Arm/Group Title | Caffeine+Saline IV+Saline Drops | Caffeine+Ibp IV+Saline Drops | Caffeine+Saline+Ketorolac Drops | Total |
---|---|---|---|---|
Arm/Group Description | Caffeine citrate IV (20 mg/kg loading dose, 5 mg/kg/day maintenance dose) plus placebo saline IV (1 ml/kg followed by 0.25 ml/kg) for 5 days plus sterile normal saline (one drop two times a day) for 14 days (n=40); Caffeine is the intervention Caffeine citrate: Caffeine citrate IV (20 mg/kg loading dose, 5 mg/kg/day maintenance dose) | Caffeine citrate as described in group 1, plus Ibuprofen (10 mg/kg loading dose followed by low dose ibuprofen 2.5 mg/kg/day) for 5 days plus sterile normal saline (one drop two times a day) for 14 days (n=40); Ibuprofen is the intervention Ibuprofen: Ibuprofen (10 mg/kg loading dose followed by low dose ibuprofen 2.5 mg/kg/day) for 5 days | Caffeine citrate plus saline IV placebo as described in group 1, and Ketorolac (Acuvail) eye drops (one drop two times a day) for 14 days (n=40); Ketorolac is the intervention Ketorolac: Ketorolac (Acuvail) eye drops (one drop two times a day) for 14 days | Total of all reporting groups |
Overall Participants | 6 | 3 | 5 | 14 |
Age (Gestational Age in Week) [Mean (Full Range) ] | ||||
Mean (Full Range) [Gestational Age in Week] |
25.5
|
26.7
|
26.6
|
26.6
|
Sex: Female, Male (Count of Participants) | ||||
Female |
2
33.3%
|
2
66.7%
|
3
60%
|
7
50%
|
Male |
4
66.7%
|
1
33.3%
|
2
40%
|
7
50%
|
Ethnicity (NIH/OMB) (Count of Participants) | ||||
Hispanic or Latino |
3
50%
|
3
100%
|
2
40%
|
8
57.1%
|
Not Hispanic or Latino |
3
50%
|
0
0%
|
3
60%
|
6
42.9%
|
Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
Race (NIH/OMB) (Count of Participants) | ||||
American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
Asian |
2
33.3%
|
0
0%
|
0
0%
|
2
14.3%
|
Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
Black or African American |
1
16.7%
|
0
0%
|
3
60%
|
4
28.6%
|
White |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
More than one race |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
Unknown or Not Reported |
3
50%
|
3
100%
|
2
40%
|
8
57.1%
|
Birth Weight (grams) (Grams) [Mean (Full Range) ] | ||||
Mean (Full Range) [Grams] |
731.7
|
1119.3
|
1020
|
917.7
|
Outcome Measures
Title | Efficacy as Measured by the Number of Participants Presenting With Retinopathy of Prematurity (ROP) and the Rate of Stages/Grade of ROP. |
---|---|
Description | ROP (all grades) will be graded using International ROP Classification and severe ROP (Stage 3+ disease) or need for laser or Avastin The rate of mild (stage 1), moderate (stage 2) and severe ROP (stages >3) will be calculated as the number of infants diagnosed with ROP over the number of infants receiving retinal examinations. The study enrolled only 14 of the projected sample of 120, and the low enrollment did not allow meaningful analyses of efficacy and safety. |
Time Frame | 50 weeks PCA +/- 7 days |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Caffeine+Saline IV+Saline Drops | Caffeine+Ibp IV+Saline Drops | Caffeine+Saline+Ketorolac Drops |
---|---|---|---|
Arm/Group Description | Caffeine citrate IV (20 mg/kg loading dose, 5 mg/kg/day maintenance dose) plus placebo saline IV (1 ml/kg followed by 0.25 ml/kg) for 5 days plus sterile normal saline (one drop two times a day) for 14 days (n=40); Caffeine is the intervention Caffeine citrate: Caffeine citrate IV (20 mg/kg loading dose, 5 mg/kg/day maintenance dose) | Caffeine citrate as described in group 1, plus Ibuprofen (10 mg/kg loading dose followed by low dose ibuprofen 2.5 mg/kg/day) for 5 days plus sterile normal saline (one drop two times a day) for 14 days (n=40); Ibuprofen is the intervention Ibuprofen: Ibuprofen (10 mg/kg loading dose followed by low dose ibuprofen 2.5 mg/kg/day) for 5 days | Caffeine citrate plus saline IV placebo as described in group 1, and Ketorolac (Acuvail) eye drops (one drop two times a day) for 14 days (n=40); Ketorolac is the intervention Ketorolac: Ketorolac (Acuvail) eye drops (one drop two times a day) for 14 days |
Measure Participants | 6 | 3 | 5 |
No ROP |
5
83.3%
|
3
100%
|
4
80%
|
Mild ROP (Stage 1) |
1
16.7%
|
0
0%
|
0
0%
|
Moderate ROP (Stage2) |
0
0%
|
0
0%
|
1
20%
|
severe ROP (stages >3) |
0
0%
|
0
0%
|
0
0%
|
Title | Number of Participants With Adverse Events as a Measure of Safety and Tolerability |
---|---|
Description | We did not reach the target number of participants needed to measure statistically reliable outcome measure. The secondary outcome measure included Intraventricular hemorrhage (Papile's criteria) and ocular examination for corneal lesions. |
Time Frame | Eye examinations was done at standard of care through discharge and once, at 50 weeks PCA. All infants underwent routine eye examination by a pediatric ophthalmologist according to the International Classification for ROP |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Caffeine+Saline IV+Saline Drops | Caffeine+Ibp IV+Saline Drops | Caffeine+Saline+Ketorolac Drops |
---|---|---|---|
Arm/Group Description | Caffeine citrate IV (20 mg/kg loading dose, 5 mg/kg/day maintenance dose) plus placebo saline IV (1 ml/kg followed by 0.25 ml/kg) for 5 days plus sterile normal saline (one drop two times a day) for 14 days (n=40); Caffeine is the intervention Caffeine citrate: Caffeine citrate IV (20 mg/kg loading dose, 5 mg/kg/day maintenance dose) | Caffeine citrate as described in group 1, plus Ibuprofen (10 mg/kg loading dose followed by low dose ibuprofen 2.5 mg/kg/day) for 5 days plus sterile normal saline (one drop two times a day) for 14 days (n=40); Ibuprofen is the intervention Ibuprofen: Ibuprofen (10 mg/kg loading dose followed by low dose ibuprofen 2.5 mg/kg/day) for 5 days | Caffeine citrate plus saline IV placebo as described in group 1, and Ketorolac (Acuvail) eye drops (one drop two times a day) for 14 days (n=40); Ketorolac is the intervention Ketorolac: Ketorolac (Acuvail) eye drops (one drop two times a day) for 14 days |
Measure Participants | 6 | 3 | 5 |
Count of Participants [Participants] |
0
0%
|
0
0%
|
1
20%
|
Title | Length of Hospital Stay |
---|---|
Description | Safety as measured by Length of hospital stay |
Time Frame | on average 6 months |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Caffeine+Saline IV+Saline Drops | Caffeine+Ibp IV+Saline Drops | Caffeine+Saline+Ketorolac Drops |
---|---|---|---|
Arm/Group Description | Caffeine citrate IV (20 mg/kg loading dose, 5 mg/kg/day maintenance dose) plus placebo saline IV (1 ml/kg followed by 0.25 ml/kg) for 5 days plus sterile normal saline (one drop two times a day) for 14 days (n=40); Caffeine is the intervention Caffeine citrate: Caffeine citrate IV (20 mg/kg loading dose, 5 mg/kg/day maintenance dose) | Caffeine citrate as described in group 1, plus Ibuprofen (10 mg/kg loading dose followed by low dose ibuprofen 2.5 mg/kg/day) for 5 days plus sterile normal saline (one drop two times a day) for 14 days (n=40); Ibuprofen is the intervention Ibuprofen: Ibuprofen (10 mg/kg loading dose followed by low dose ibuprofen 2.5 mg/kg/day) for 5 days | Caffeine citrate plus saline IV placebo as described in group 1, and Ketorolac (Acuvail) eye drops (one drop two times a day) for 14 days (n=40); Ketorolac is the intervention Ketorolac: Ketorolac (Acuvail) eye drops (one drop two times a day) for 14 days |
Measure Participants | 6 | 3 | 5 |
Mean (Standard Deviation) [Days] |
126
(30.1)
|
74
(9.0)
|
68
(21.8)
|
Adverse Events
Time Frame | The adverse events data were collected over an average of 6 months. | |||||
---|---|---|---|---|---|---|
Adverse Event Reporting Description | ||||||
Arm/Group Title | Caffeine+Saline IV+Saline Drops | Caffeine+Ibp IV+Saline Drops | Caffeine+Saline+Ketorolac Drops | |||
Arm/Group Description | Caffeine citrate IV (20 mg/kg loading dose, 5 mg/kg/day maintenance dose) plus placebo saline IV (1 ml/kg followed by 0.25 ml/kg) for 5 days plus sterile normal saline (one drop two times a day) for 14 days (n=40); Caffeine is the intervention Caffeine citrate: Caffeine citrate IV (20 mg/kg loading dose, 5 mg/kg/day maintenance dose) | Caffeine citrate as described in group 1, plus Ibuprofen (10 mg/kg loading dose followed by low dose ibuprofen 2.5 mg/kg/day) for 5 days plus sterile normal saline (one drop two times a day) for 14 days (n=40); Ibuprofen is the intervention Ibuprofen: Ibuprofen (10 mg/kg loading dose followed by low dose ibuprofen 2.5 mg/kg/day) for 5 days | Caffeine citrate plus saline IV placebo as described in group 1, and Ketorolac (Acuvail) eye drops (one drop two times a day) for 14 days (n=40); Ketorolac is the intervention Ketorolac: Ketorolac (Acuvail) eye drops (one drop two times a day) for 14 days | |||
All Cause Mortality |
||||||
Caffeine+Saline IV+Saline Drops | Caffeine+Ibp IV+Saline Drops | Caffeine+Saline+Ketorolac Drops | ||||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 0/6 (0%) | 0/3 (0%) | 2/5 (40%) | |||
Serious Adverse Events |
||||||
Caffeine+Saline IV+Saline Drops | Caffeine+Ibp IV+Saline Drops | Caffeine+Saline+Ketorolac Drops | ||||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 6/6 (100%) | 3/3 (100%) | 2/5 (40%) | |||
Congenital, familial and genetic disorders | ||||||
Patent ductus arteriosus (PDA) | 2/6 (33.3%) | 1/3 (33.3%) | 0/5 (0%) | |||
Gastrointestinal disorders | ||||||
Death | 0/6 (0%) | 0 | 0/3 (0%) | 0 | 2/5 (40%) | 2 |
Necrotizing enterocolitis (NEC) | 0/6 (0%) | 0/3 (0%) | 2/5 (40%) | |||
Nervous system disorders | ||||||
Intraventricular hemorrhage (IVH) | 0/6 (0%) | 0/3 (0%) | 1/5 (20%) | |||
Respiratory, thoracic and mediastinal disorders | ||||||
Apnea | 6/6 (100%) | 3/3 (100%) | 2/5 (40%) | |||
Bronchopulmonary dysplasia (BPD | 1/6 (16.7%) | 0/3 (0%) | 2/5 (40%) | |||
Other (Not Including Serious) Adverse Events |
||||||
Caffeine+Saline IV+Saline Drops | Caffeine+Ibp IV+Saline Drops | Caffeine+Saline+Ketorolac Drops | ||||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 6/6 (100%) | 3/3 (100%) | 5/5 (100%) | |||
Respiratory, thoracic and mediastinal disorders | ||||||
Respiratory Distress Syndrome (RDS) | 6/6 (100%) | 3/3 (100%) | 5/5 (100%) |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title | Jacob V. Aranda, MD, PhD, FRCPC, Principal Investigator |
---|---|
Organization | SUNY Downstate Medical Center |
Phone | 718-270-1912 |
jaranda@downstate.edu |
- 349622
- 1U54HD071594