Inositol to Reduce Retinopathy of Prematurity (INS-3)
|ClinicalTrials.gov Identifier: NCT01954082|
Recruitment Status : Terminated (Study terminated due to safety concerns; participant follow up will continue until March 2018)
First Posted : October 1, 2013
Last Update Posted : September 26, 2017
|Condition or disease||Intervention/treatment||Phase|
|Retinopathy of Prematurity (ROP)||Drug: myo-Inositol 5% Injection Drug: Placebo||Phase 3|
Approximately 1760 infants are to be enrolled at approximately 18 NICHD Neonatal Research Network (NRN) Centers (approximately 44 sites) in the United States. Infants meeting the study selection criteria and for whom informed consent is obtained will be randomized to receive either 80 mg inositol/kg/day or placebo, administered in divided doses every 12 hours (40 mg/kg/dose). Study drug will be administered daily, starting within 12 to 72 hours of birth and continued until the earliest of 34 weeks PMA, 10 weeks chronologic age, or the time of hospital discharge or transfer. Inositol or placebo will be administered IV until enteral feedings reach 120ml/kg/day (or sooner if the infant is no longer receiving IV fluids), at which time the same dose and formulation will be administered enterally every 12 hours.
For publication purposes, the analysis of the primary efficacy outcome will consider the entire study population. In support of a new drug application (NDA) for use of myo-Inositol 5% Injection to increase survival without severe ROP through the determination of acute/final ROP status, the analysis of the primary efficacy outcome will be conducted for the entire study population and separately within pre-specified regulatory sub-studies created by administratively splitting infants enrolled at each study center into two sub-studies.
Assessments performed during the study include customary newborn intensive care procedures including repeat eye examinations until ROP status is final (which often extends after discharge), measurements of growth, cranial ultrasounds or other imaging per usual practice, and the collection of clinical diagnoses throughout hospitalization to evaluate other common morbidities of extreme preterm birth. Adverse events will be recorded from time of treatment initiation until 7 days after the last dose of study drug, and concurrent medications will be recorded from 24 hours prior to randomization until 7 days after the last dose of study drug or until discharge or transfer if sooner. Using the separate NICHD Follow-up protocol, longer term data will be collected at 22-26 months corrected age, including growth, neurodevelopmental testing, overall health status, rehospitalizations, surgeries and diagnoses, including ophthalmic diagnoses and treatments since discharge.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||638 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)|
|Official Title:||INS-3: A Phase 3, Randomized, Double-Masked, Placebo-Controlled Study of the Efficacy and Safety of Myo-Inositol 5% Injection to Increase Survival Without Severe Retinopathy of Prematurity (Reduce-ROP) in Extremely Premature Infants|
|Study Start Date :||April 2014|
|Primary Completion Date :||December 31, 2016|
|Estimated Study Completion Date :||April 30, 2018|
Experimental: myo-Inositol 5% Injection
Within 12-72 hours of birth, infants will receive 80 mg myo-inositol 5% Injection per kilogram per day, administered in divided doses every 12 hours (40 mg/kg/dose). Study drug will be administered daily and continued until the earliest of 34 completed weeks PMA, 10 weeks (70 days) chronologic age, or the time of discharge. myo-Inositol 5% Injection will be administered IV until enteral feedings are established, at which time the same dose and formulation will be administered enterally every 12 hours.
Drug: myo-Inositol 5% Injection
Abbott Nutrition Division, Abbott Laboratories is supplying myo-Inositol 5% Injection to the clinical centers for the duration of the trial.
Inositol: myo-Inositol 5% Injection is an isotonic, preservative-free, sterile 5% solution of myo-inositol in water containing 0.5 gm sodium chloride per liter (8.55mM), pH 6.5-7.5. It is administered via IV infusion using syringe pump over 15-30 minutes twice per day at 12-hour intervals at a dose of 80 mg inositol/kg/day (40 mg inositol/kg/dose), which is equivalent to 1.6 mL/kg/day (0.80 mL/kg/dose).
Other Name: Inositol
Placebo Comparator: 5% glucose(dextrose)
Within 12-72 hours of birth, infants will receive 80 mg 5% glucose(dextrose) USP for intravenous infusion per kilogram per day, administered in divided doses every 12 hours (40 mg/kg/dose). Study drug will be administered daily and continued until the earliest of 34 completed weeks PMA, 10 weeks (70 days) chronologic age, or the time of discharge. myo-Inositol 5% Injection will be administered IV until enteral feedings are established, at which time the same dose and formulation will be administered enterally every 12 hours.
- Survival without severe Retinopathy of Prematurity (ROP) through Acute/Final ROP status determination (favorable) versus development of severe ROP or death prior to reaching Acute/Final ROP status (unfavorable) followed up to 55 weeks PMA. [ Time Frame: by 55 weeks PMA ]
- Death in relation to the primary variable will be defined as from any cause before Acute/Final ROP status is determined.
- Favorable Acute/Final ROP status requires that no ROP, or only mild ROP has occurred in both eyes and that the eyes have matured beyond the risk of developing severe ROP.
- Unfavorable ROP determination requires that one or both eyes reach ROP severity warranting intervention.
Since an estimated 5 to 8 percent of primary outcomes are expected to be missing primarily due to final acute ROP status not being determined by 55 weeks (favorable or unfavorable status), where possible, for the primary analysis for publication an adjudication process will be used to determine final acute status for those with incomplete or missing final acute ROP status. This assessment will be used in defining the survival without sROP (favorable vs. unfavorable ROP status).
Thus, information on both survival and ROP status are necessary to obtain the primary outcome
- Bronchopulmonary Dysplasia (BPD) [ Time Frame: 36 weeks PMA ]NICHD Physiologic Definition: Requiring oxygen to maintain an oxygen saturation of 90% or greater while breathing room air at 36 weeks PMA
- BPD or Death from BPD [ Time Frame: prior to 37 weeks PMA ]BPD (Physiologic Definition) or Death from BPD prior to 37 weeks PMA, with cause of death certified by the Center PI as the primary cause, or a significant co-contributing cause of death.
- All cause death [ Time Frame: 22 - 26 months age ]Defined as death from any cause following randomization
- Any ROP [ Time Frame: by 55 weeks PMA ]Any ROP: defined as ROP of any severity that is observed on at least 2 examinations in either eye through the time that Acute/Final ROP status is reached.
- Type 2 ROP [ Time Frame: by 55 weeks PMA ]
Type 2 ROP through the time that Acute/Final ROP status is reached: defined as 1 or both eyes reaching Type 2 ROP (ETROP 2003), but not Type 1.
Type 2 ROP is defined as: (ETROP 2003).
- in Zone II: Stage 3 ROP without Plus Disease, or
- in Zone I: Stage 1 or 2 ROP without Plus Disease
- Severe IVH [ Time Frame: approximately 1 to 6 weeks after birth ]IVH Grades 3 or 4 on either side of the brain, or extensive PVL. IVH will be classified as described by Papile (Papile 1978). PVL will be graded by the characteristics of the periventricular white matter on ultrasound or MRI done between 4 to approximately 6 weeks after birth per usual care (Barkovich 2000) and/or porencephalic cyst.
- The occurrence of adverse events and serious adverse events [ Time Frame: 7 days post study drug discontinuation ]
- Necrotizing Enterocolitis (NEC) [ Time Frame: NRN infant status, i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth ]Stage II or worse, whether treated (medically or surgically) and if the infant survived (modified Bell's classification [Walsh 1986]).
- Isolated gastrointestinal perforation [ Time Frame: NRN infant status, i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth ]judged not to be due to NEC
- Late onset sepsis [ Time Frame: NRN infant status, i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth ]culture positive septicemia/bacteremia (≥72 hours of age) treated with antibiotics for ≥ 5 days or died before treatment was completed.
- Patent Ductus Arteriosus (PDA) [ Time Frame: NRN infant status, i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth ]Occurrence of clinically significant patent ductus arteriosus (PDA), and if received intervention with prostaglandin inhibitors, and/or surgery.
- Seizures [ Time Frame: NRN infant status, i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth ]Seizures treated with an anticonvulsant for >72 hours
- Total days on parenteral nutrition [ Time Frame: NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth ]Total days on parenteral nutrition (including amino acids and/or lipids)
- Days on oxygen, days on ventilator [ Time Frame: NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth ]
- Hearing Loss [ Time Frame: NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth ]Hearing loss as defined as never passing a hearing screening in one or both ears
- Neurodevelopment [ Time Frame: 22-26 months corrected age ]Neurodevelopment at 22-26 months corrected age (i.e., 22-26 months past due date) using the Bayley Scales of Infant Development III.
- Vision loss [ Time Frame: 22-26 Months Corrected Age ]Vision loss as diagnosed by an ophthalmologist as legally blind, and subdivided into "ophthalmic origin", or "not ophthalmic origin" (i.e., cortical blindness is non-ophthalmic in origin and indicates that there is no retinal detachment or other abnormal fundus or ocular finding, except optic atrophy. Such cases will be considered central [neurologic] in origin.)
- Hearing loss [ Time Frame: 22-26 Months Corrected Age ]Hearing loss requiring that hearing aids be prescribed.
- Cerebral palsy [ Time Frame: 22-26 Months Corrected Age ]Cerebral palsy by severity category (absent/mild/moderate/severe).
- Overall health status [ Time Frame: 22-26 Months Corrected Age ]Overall health status per recall from the parent/guardian (including survival, re-hospitalizations, surgeries, ongoing medications, and chronic illnesses).
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01954082
|United States, Alabama|
|University of Alabama at Birmingham|
|Birmingham, Alabama, United States, 35233|
|United States, California|
|University of California - Los Angeles|
|Los Angeles, California, United States, 90025|
|Palo Alto, California, United States, 94304|
|United States, Georgia|
|Atlanta, Georgia, United States, 30303|
|United States, Indiana|
|Indianapolis, Indiana, United States, 46202|
|United States, Iowa|
|University of Iowa|
|Iowa City, Iowa, United States, 52242|
|United States, Michigan|
|Wayne State University|
|Detroit, Michigan, United States, 48201|
|United States, Missouri|
|Children's Mercy Hospital|
|Kansas City, Missouri, United States, 64108|
|United States, New Mexico|
|University of New Mexico|
|Albuquerque, New Mexico, United States, 87131|
|United States, New York|
|University of Rochester|
|Rochester, New York, United States, 14642|
|United States, North Carolina|
|Durham, North Carolina, United States, 27705|
|Durham, North Carolina, United States, 27710|
|United States, Ohio|
|Cincinnati Children's Medical Center|
|Cincinnati, Ohio, United States, 45267|
|Case Western Reserve University, Rainbow Babies and Children's Hospital|
|Cleveland, Ohio, United States, 44106|
|Research Institute at Nationwide Children's Hospital|
|Columbus, Ohio, United States, 43205|
|United States, Pennsylvania|
|Univeristy of Pennsylvania|
|Philadelphia, Pennsylvania, United States, 19104|
|United States, Rhode Island|
|Brown University, Women & Infants Hospital of Rhode Island|
|Providence, Rhode Island, United States, 02905|
|United States, Texas|
|University of Texas Southwestern Medical Center at Dallas|
|Dallas, Texas, United States, 75235|
|University of Texas Health Science Center at Houston|
|Houston, Texas, United States, 77030|
|Principal Investigator:||Michele C Walsh, MD||Case Western Reserve University, Rainbow Babies and Children's Hospital|
|Principal Investigator:||Abhik Das, PhD||RTI International|
|Principal Investigator:||Seetha Shankaran, MD||Wayne State University|
|Principal Investigator:||Barbara J Stoll, MD||Emory University|
|Principal Investigator:||Kurt Schibler, MD||Children's Hospital Medical Center, Cincinnati|
|Principal Investigator:||Greg Sokol, MD||Indiana University|
|Principal Investigator:||Abbot R Laptook, MD||Brown University, Women & Infants Hospital of Rhode Island|
|Principal Investigator:||Krisa P Van Meurs, MD||Stanford University|
|Principal Investigator:||Waldemar A Carlo, MD||University of Alabama at Birmingham|
|Principal Investigator:||Kathleen A Kennedy, MD, MPH||The University of Texas Health Science Center, Houston|
|Principal Investigator:||Ronald N Goldberg, MD||Duke University|
|Principal Investigator:||Edward F Bell, MD||University of Iowa|
|Study Director:||Dale L Phelps, MD||University of Rochester|
|Principal Investigator:||Carl T D'Angio, MD||University of Rochester|
|Principal Investigator:||William Truog, MD||Children's Mercy Hospital Kansas City|
|Principal Investigator:||Pablo Sanchez, MD||Research Institute at Nationwide Children's Hospital|
|Principal Investigator:||Uday Devaskar, MD||University of California, Los Angeles|
|Principal Investigator:||Myra Wyckoff, MD||University of Texas at Southwestern|
|Principal Investigator:||Kristi L Watterberg, MD||University of New Mexico|
|Principal Investigator:||Barbara Schmidt, MD||University of Pennsylvania|