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Infant, NewbornPhase 2INS-2NCT01030575

Multi-dose Pharmacokinetics and Dose Ranging of Inositol in Premature Infants (INS-2)

A Phase 2 study testing Inositol lower volume, Inositol mid-level volume and Inositol high volume in people with Infant, Newborn and Infant, Low Birth Weight, run by NICHD Neonatal Research Network at 17 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

This pilot study is a randomized, placebo-controlled, clinical trial to measure changes in blood and urine levels of inositol in premature infants at high risk for retinopathy of prematurity (ROP) following repeated doses of inositol. Read more about this study

Who is it for?
Ages 12 to 72 hoursHealthy volunteers can take part
What is being tested?
Inositol lower volume, Inositol mid-level volume and Inositol high volume
Type of treatment
Injection or infusion
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
125 participants
Where
17 sitesUnited States
Study dates
Jan 2010to Sep 2013
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 12 to 72 hours
  • All sexes
  • Healthy volunteers accepted
  • Child

Who may be able to join

  • 23 0/7 to 26 6/7 weeks gestational age (48 infants) or
  • 27 0/7 to 29 6/7 weeks gestational age (48 infants)
  • 401 grams birth weight or larger
  • 12-72 hours of age

Who cannot join

  • Major congenital and intracranial anomalies
  • Moribund or not to be provided continued support
  • Seizures
  • Suspected renal failure (oliguria <0.6 cc/kg/hr for >24 hours or creatinine >2.5 mg/dL)

Trial locations and contacts

17 sites in 1 country.

17 sites in 1 country

United States17 sites

  • University of New Mexico

    Albuquerque, New Mexico, 87131

  • Emory University

    Atlanta, Georgia, 30303

  • University of Alabama at Birmingham

    Birmingham, Alabama, 35233

  • Tufts Medical Center

    Boston, Massachusetts, 02111

  • Case Western Reserve University, Rainbow Babies and Children's Hospital

    Cleveland, Ohio, 44106

  • University of Texas Southwestern Medical Center at Dallas

    Dallas, Texas, 75235

  • Wayne State University

    Detroit, Michigan, 48201

  • RTI International

    Durham, North Carolina, 27705

  • Duke University

    Durham, North Carolina, 27710

  • University of Texas Health Science Center at Houston

    Houston, Texas, 77030

  • Indiana University

    Indianapolis, Indiana, 46202

  • University of Iowa

    Iowa City, Iowa, 52242

  • Yale University

    New Haven, Connecticut, 06504

  • Stanford University

    Palo Alto, California, 94304

  • Brown University, Women & Infants Hospital of Rhode Island

    Providence, Rhode Island, 02905

  • University of Rochester

    Rochester, New York, 14642

  • University of Utah

    Salt Lake City, Utah, 84108

Other trials in United States

About this study

Official title: Phase II Randomized, Double-Masked, Placebo-Controlled, Safety, Pharmacokinetic, and Dose-Ranging Study of Multiple Doses of Inositol in Premature Infants

This pilot study is a randomized, placebo-controlled, clinical trial to measure changes in blood and urine levels of inositol in premature infants at high risk for retinopathy of prematurity (ROP) following repeated doses of inositol. Based on previous studies, the premise is that maintaining inositol concentrations similar to those occurring naturally in utero will reduce the rates of ROP and bronchopulmonary dysplasia in premature infants. The objective is to evaluate pharmacokinetics, safety, and clinical outcomes of multiple doses of three different dose amounts of myo-inositol (provided by Abbott Laboratories) in very low birth weight premature infants. This study will enroll an estimated 96 infants at 17 NICHD Neonatal Research Network sites. Infants will be randomly assigned to receive either 10 mg/kg of 5% inositol, 40 mg/kg of 5% inositol, 80 mg/kg of 5% inositol, or 5% glucose given in the same volumes and timings as the inositol dosage to maintain masking. Enrollees will receive their assigned dose or placebo daily, starting within 72 hours of birth, and continuing until they reach 34 weeks post-menstrual age, 10 weeks chronologic age, or until the time of hospital discharge, whichever occurs first. The study drug will be administered first intravenously; as the infants progress to full feeding, the drug will be given enterally (orally or via feeding tube). Enrollees will be seen for a follow-up examination at 18-22 months corrected age. This pilot study is in preparation for a future Phase III multi-center randomized controlled trial.

Read the detailed description

Retinopathy of prematurity (ROP) is an abnormal growth of the blood vessels in the eye that occurs primarily in very premature infants. Eye development occurs normally in the womb; in infants born prematurely, however, the blood vessels must finish developing outside the protective environment of the uterus. Retinopathy of prematurity (also known as retrolental fibroplasia) is a leading cause of blindness and other vision impairments (myopia, strabismus, and amblyopia) in children, both in developed and developing countries.

Inositol is a naturally-occurring sugar alcohol produced by the fetus and placenta and is present in high levels in fetal blood throughout pregnancy in humans and other animals. Serum levels fall rapidly after birth, although this fall is moderated in infants who receive breast milk or fortified formula. Two randomized trials have shown that intravenous inositol supplementation in the first week significantly reduced death, bronchopulmonary dysplasia (BPD), and retinopathy. One study of enteral supplements (given orally or via feeding tube) was less convincing, but also supported reduction of retinopathy.

This pilot study will evaluate changes in blood and urine inositol levels (half-life pharmacokinetics) of multiple doses of myo-inositol (provided by Abbott Laboratories, Abbott Nutrition Division) given to very low birth weight infants. The premise is that maintaining inositol concentrations similar to those occurring naturally in utero will reduce the rates of retinopathy and bronchopulmonary dysplasia in premature infants. Results from this study will be used to select the dose for a large multi-center trial.

In this study, 17 NICHD Neonatal Research Network sites will enroll approximately 96 infants at 12-72 hours of age. Enrolled infants will be randomly assigned to receive either 10mg/kg of 5% inositol, 40 mg/kg of 5% inositol, 80 mg/kg of 5% inositol, or 5% glucose given in the same volumes and timings as the inositol dosage to maintain masking. Inositol will be administered intravenously until babies are feeding normally, at which time the same dose and formulation will be administered enterally (orally or via feeding tube). Concentrations of inositol will be measured in blood, urine, and milk received.

Stratification: Recruitment will be stratified by gestational age into infants born at 23 0/7 to 26 6/7 weeks gestational age and infants born at 27 0/7 to 29 6/7 weeks gestational age.

Being tested
Inositol lower volume, Inositol mid-level volume, Inositol high volume, Placebo low volume
Keywords
NICHD Neonatal Research Network, Pharmacokinetics, Inositol, Very Low Birth Weight (VLBW), Extremely Low Birth Weight (ELBW), Prematurity
Medical subject headings
Premature Birth, Retinopathy of Prematurity, Bronchopulmonary Dysplasia

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Inositol lower volumeDrug

    Also called Myo-inositol 5%

    5 mg/kg/dose inositol every 12 hours, given intravenously over 20 minutes

  • Inositol mid-level volumeDrug

    Also called Myo-inositol 5%

    20 mg/kg/dose inositol every 12 hours, given intravenously over 20 minutes

  • Inositol high volumeDrug

    Also called Myo-inositol 5%

    40 mg/kg/dose inositol every 12 hours, given intravenously over 20 minutes

  • Placebo low volumeDrug

    Also called Dextrose

    Glucose 5% given in volumes equal to that of the comparator drug

Study groups in NCT01030575
Study groupRoleWhat they receive
Inositol low volumeExperimental10 mg/kg/day Intravenous inositol 5%
Receives: Drug: Inositol lower volume
Inositol mid-level volumeExperimental40 mg/kg/day Intravenous inositol 5%
Receives: Drug: Inositol mid-level volume
Inositol high volumeExperimental80 mg/kg/day Intravenous inositol 5%
Receives: Drug: Inositol high volume
PlaceboPlacebo comparatorGlucose 5% given in volumes equal to that of the comparator drug
Receives: Drug: Placebo low volume

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Population Pharmacokinetics: V - Volume

    Measured: 8-10 blood samples per infant were drawn over 10 weeks for infant safety with the full study duration represented across all infants. Samples were drawn at baseline & on days 1, 2, 4, 6, 8, 10, 12, 14, 16, 20, 24, 28, 35, 42, 56, and 70.

  2. Population Pharmacokinetics: Cl - Clearance

    Measured: 8-10 blood samples per infant were drawn over 10 weeks for infant safety with the full study duration represented across all infants. Samples were drawn at baseline & on days 1, 2, 4, 6, 8, 10, 12, 14, 16, 20, 24, 28, 35, 42, 56, and 70.

  3. Population Pharmacokinetics: R - Endogenous Infusion Rate

    Measured: 8-10 blood samples per infant were drawn over 10 weeks for infant safety with the full study duration represented across all infants. Samples were drawn at baseline & on days 1, 2, 4, 6, 8, 10, 12, 14, 16, 20, 24, 28, 35, 42, 56, and 70.

  4. Population Pharmacokinetics: k - Elimination Rate (Cl/V)

    Measured: 8-10 blood samples per infant were drawn over 10 weeks for infant safety with the full study duration represented across all infants. Samples were drawn at baseline & on days 1, 2, 4, 6, 8, 10, 12, 14, 16, 20, 24, 28, 35, 42, 56, and 70.

  5. Population Pharmacokinetics: t1/2 - Half-Life (0.693/k)

    Measured: 8-10 blood samples per infant were drawn over 10 weeks for infant safety with the full study duration represented across all infants. Samples were drawn at baseline & on days 1, 2, 4, 6, 8, 10, 12, 14, 16, 20, 24, 28, 35, 42, 56, and 70.

  6. Population Pharmacokinetics: E - Concentration Due to Endogenous Infusion (R/Cl)

    Measured: 8-10 blood samples per infant were drawn over 10 weeks for infant safety with the full study duration represented across all infants. Samples were drawn at baseline & on days 1, 2, 4, 6, 8, 10, 12, 14, 16, 20, 24, 28, 35, 42, 56, and 70.

  7. SD of Residual Error (mg/l)

    Measured: 8-10 blood samples per infant were drawn over 10 weeks for infant safety with the full study duration represented across all infants. Samples were drawn at baseline & on days 1, 2, 4, 6, 8, 10, 12, 14, 16, 20, 24, 28, 35, 42, 56, and 70.

Secondary outcomes (14)

  1. Number of Participants With Any Retinopathy of Prematurity (ROP)

    Any ROP is defined as ROP of any severity that is observed at 18-22 month corrected age

    Measured: 18-22 month corrected age

  2. Number of Participants With Any Retinopathy of Prematurity Through 18-22 Month Corrected Age or Death

    Number of participants with any Retinopathy of Prematurity (ROP) through 18-22 month corrected age or death

    Measured: 18-22 month corrected age

  3. Number of Participants With Any Ophthalmologic Diagnosis

    Any ophthalmologic diagnosis at 18-22 month corrected age

    Measured: 18-22 month corrected age

  4. Number of Participants With Any Ophthalmologic Treatment

    Any ophthalmologic treatment at 18-22 month corrected age

    Measured: 18-22 month corrected age

  5. Number of Participants With Any Ophthalmologic Surgical Treatment

    Any ophthalmologic surgical treatment at 18-22 month corrected age

    Measured: 18-22 month corrected age

  6. Number of Participants With Any Ophthalmologic Medical Treatment

    Any ophthalmologic medical treatment at 18-22 month corrected age

    Measured: 18-22 month corrected age

  7. Number of Participants With Moderate or Severe Neurodevelopmental Impairment at 18-22 Month Corrected Age

    A composite outcome that measures the occurrence of neurodevelopmental impairment between birth and 18-22 months corrected age.

    Measured: 18-22 month corrected age

  8. Number of Participants With Moderate or Severe Neurodevelopmental Impairment at 18-22 Month Corrected Age or Death

    Moderate or Severe NDI defined as occurrence of any of the following: GMFCS level II or higher (severe is level 4 or 5), Bayley III cognitive composite score < 85 (severe is <70), Bayley III motor composite score < 85 (severe is <70), unilateral blind or bilateral blind, permanent hearing loss that does not permit child to understand directions of the examiner and communicate despite amplification with cochlear implant or hearing aid

    Measured: 8-22 months corrected age.

  9. Number of Participants With Moderate or Severe Cerebral Palsy

    Cerebral palsy by severity category (absent/mild/moderate/severe).

    Measured: 18-22 months corrected age.

  10. Number of Participants With Composite Motor Score Less Than 70

    This is measured as a scored of less than 70 on the Bayley Scale of Infant and Toddler Development (BSID)-III composite motor score. Higher scores indicate better performance.

    Measured: 18-22 months corrected age

  11. Number of Participants With Composite Cognitive Score Less Than 70

    This is measured as a score of less than 70 on the Bayley Scale of Infant and Toddler Development (BSID)-III composite cognitive score

    Measured: 18-22 months corrected age.

  12. Number of Participants With Severe Hearing Impairment

    Defined as permanent hearing loss that does not permit child to understand directions of the examiner and communicate despite amplification with cochlear implant or hearing aid.

    Measured: 18-22 months corrected age.

  13. Number of Participants With Severe Vision Loss

    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.)

    Measured: 18-22 Months Corrected Age

  14. Number of Participants With Gross Motor Function Greater Than or Equal to 2

    A Gross Motor Function Classification System (GMFCS) level of at least II (on a scale from level I to V, with I indicating normal gross motor function and higher levels indicating greater impairment). Level II is defined as Infants maintain floor sitting but may need to use their hands for support to maintain balance. Infants creep on their stomach or crawl on hands and knees with reciprocal leg movement. Infants may pull to stand and take steps holding on to furniture.)

    Measured: 18 -22 months corrected age

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted11 Dec 2009 (estimated)
  2. Study startJan 2010
  3. Primary completionMay 2011
  4. Study completionSep 2013

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Prevention
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
125 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01030575
Sponsor's protocol ID
NICHD-NRN-0036-2
Other IDs
U10HD021364, U10HD021373, U10HD021385, U10HD027851, U10HD027853, U10HD027856, U10HD027871, U10HD027880
Acronym
INS-2
Status last verified
Mar 2022
First submitted
10 Dec 2009
Last updated
14 Jun 2022
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: NDASG

Publications

  • Phelps DL, Ward RM, Williams RL, Nolen TL, Watterberg KL, Oh W, Goedecke M, Ehrenkranz RA, Fennell T, Poindexter BB, Cotten CM, Hallman M, Frantz ID 3rd, Faix RG, Zaterka-Baxter KM, Das A, Ball MB, Lacy CB, Walsh MC, Carlo WA, Sanchez PJ, Bell EF, Shankaran S, Carlton DP, Chess PR, Higgins RD. Safety and pharmacokinetics of multiple dose myo-inositol in preterm infants. Pediatr Res. 2016 Aug;80(2):209-17. doi: 10.1038/pr.2016.97. Epub 2016 Apr 13.

    PubMed 27074126

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Inositol lower volume, Inositol mid-level volume and Inositol high volume in people with Infant, Newborn and Infant, Low Birth Weight, run by NICHD Neonatal Research Network at 17 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 4 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 14 Jun 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 17 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 12 Mar 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Population Pharmacokinetics: V - Volume (time frame: 8-10 blood samples per infant were drawn over 10 weeks for infant safety with the full study duration represented across all infants. Samples were drawn at baseline & on days 1, 2, 4, 6, 8, 10, 12, 14, 16, 20, 24, 28, 35, 42, 56, and 70.). The study lists 7 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01030575, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Jun 2022.

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