Comparing Ibuprofen And Indomethacin For The Treatment Of The Patent Ductus Arteriosus in Very Premature Babies

Ductus Arteriosus, Patent Clinical Trial

Official title:

A Randomised Controlled Trial Comparing Ibuprofen And Indomethacin For The Treatment Of The Patent Ductus Arteriosus In Very Premature Infants

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT00470743
• Other study ID #: SQPDA02
• Status: Withdrawn
• Phase: Phase 4
• First received: May 7, 2007
• Last updated: September 1, 2015
• Start date: May 2007
• Est. completion date: June 2009

Study information

• Verified date: June 2009
• Source: KK Women's and Children's Hospital
• Contact: n/a
• Is FDA regulated: No
• Health authority: Singapore: Health Sciences Authority
• Study type: Interventional

Clinical Trial Summary

The purpose of the study is to determine the safety and efficacy of ibuprofen, compared with indomethacin, in the treatment for the closure of the patent ductus arteriosus in premature babies born under 29 weeks gestation

Description:

According to Very Low Birth Weight (VLBW) High Risk Registration database in KKWCH, a hemodynamically significant patent ductus arteriosus (PDA) is a common problem in very premature infants born at a gestational age of 29 weeks and under, with more than 50% of them needing indomethacin treatment for closure of the PDA.

Prostaglandins play a major role in keeping the ductus patent . Indomethacin, because of its anti-prostaglandin effect via inhibition of the prostaglandin forming cyclo-oxygenase enzymes, has been used to medically close the PDA since the 1970s. Concerns with this drug relate to its effect on cerebral, renal and gastrointestinal blood flow. Necrotising enterocolitis (NEC), gastrointestinal perforation, gastrointestinal bleeding, transient or permanent renal impairment and reduced cerebral blood flow have been associated with indomethacin.

Ibuprofen treatment for PDA have been reported in the 1990s. It is as effective as indomethacin in closing the PDA. It is potentially better than indomethacin because regional blood flows were not affected. The few trials that have been done comparing intravenous ibuprofen and indomethacin involved mainly heavier very low birth weight (VLBW) infants. In a New England Journal of Medicine editorial on this subject, Clyman pointed out the need for trials involving the very immature infants to look at efficacy and safety.

The main obstacle for ibuprofen use in premature infants is the absence of a commercially available intravenous preparation. In our proposed trial a new i.v. ibuprofen preparation manufactured by Cumberland Pharmaceuticals (Nashville, Tennessee) will be used.

A Cochrane systematic review on ibuprofen for the treatment of PDA in premature infants concluded that it performed with the same effectiveness when compared to indomethacin. There was a significant decrease in the incidence of oliguria in the ibuprofen arm, with a higher risk of chronic lung disease at 28 days of life (borderline statistical significance), but not at 36 weeks.There is no biologically plausible explanation for the latter effect and this could be attributed to chance in view of this, plus the weak statistical proof. The other problem with this review was that it included trials where enteral ibuprofen was used, and this route is clearly impractical in the very premature infants which we plan to study because of the unpredictable absorption from the immature gut and their general intolerance to feeding at such an early age. The concern regarding pulmonary hypertension with the prophylactic use of ibuprofen also should not apply to our planned study where the time of administration of the drugs will be around 24 hours of age.

The potential benefits stemming from ibuprofen's biological advantage over indomethacin will be reduction in the rates of oliguria, gastrointestinal bleeding, NEC and gastrointestinal perforation. NEC and gastrointestinal perforation are conditions with serious morbidities and usually result in prolonged hospital stay and poorer neurodevelopmental outcome for the affected infants. A better drug could lead to cost savings.

Neurosensory impairment is an important outcome to monitor because indomethacin reduces cerebral blood flow. This point was also emphasized in the Cochrane systematic review mentioned above. However this will be the subject of another proposal in view of the significant additional budget needed.

The objective of the trial is to compare, the the safety and efficacy of intravenous ibuprofen treatment for the closure of the patent ductus arteriosus diagnosed via 2D echocardiography in very premature babies born under 29 weeks of gestation, with traditional therapy indomethacin.

The primary outcome measure will be the incidence of oliguria and gastric bleeding within one week after the 1st dose of treatment

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: June 2009
• Est. primary completion date: June 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 29 Weeks

Eligibility

Inclusion Criteria:

• Infants <29 weeks gestation with a PDA diameter of >= 1.5 mm on 2Dechocardiogram

• Parental written informed consent - Parent agrees to the subject's participation in the study as indicated by parent's signature on the consent form

• Parent is willing to comply with procedures/treatment and is able to keep to scheduled study assessments

Exclusion criteria:

• Major congenital malformations in the opinion of the investigator

• Necrotising enterocolitis

• Gastrointestinal Perforation

• Systemic illness other than PDA, not fit for the trial in the opinion of the investigator

• The parent is in the opinion of the investigator, mentally or legally incapacitated

• The parent is unwilling/unable to comply to study procedures

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Birth Weight
• Ductus Arteriosus, Patent
• Very Low Birth Weight Infants

Intervention

Drug:
• Ibuprofen

• Indomethacin

Locations

Country	Name	City	State
Singapore	KK Women's and Children's Hospital / National University Hospital	Singapore

Sponsors (3)

Lead Sponsor	Collaborator
KK Women's and Children's Hospital	Cumberland Pharmaceuticals, National University Hospital, Singapore

Country where clinical trial is conducted

Singapore, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of oliguria and gastric bleeding		within one week of treatment	Yes
Secondary	PDA closure rates after medical treatment at time of discharge from hospital		after 1 to 2 courses of treatment	No
Secondary	Need for repeat of the second course of medication		48 hrs after 3rd dose of treatment	No
Secondary	Need for surgical closure		after 1 to 2 courses of treatment	No
Secondary	In-hospital mortality		while in-hospital	Yes
Secondary	Creatinine >140umol/L within one week after the 1st dose of treatment		one week after 1st dose of treatment	Yes
Secondary	Hyponatremia within one week after the 1st dose of treatment		one week after 1st dose of treatment	Yes
Secondary	Gastrointestinal perforation within one week after the 1st dose of treatment		within one week after the 1st dose of treatment	Yes
Secondary	Necrotising enterocolitis within one week after the 1st dose of treatment		within one week after the 1st dose of treatment	Yes
Secondary	Worst grade of IVH by Day 28 of life		Day 28 of life	Yes
Secondary	Pulmonary hypertension within 48hrs after 1st dose of treatment		within 48hrs after 1st dose of treatment	Yes
Secondary	Chronic lung disease		Day 28 and corrected age of 36 weeks post-menstrual age	No
Secondary	Cystic periventricular leukomalacia at day 28 of life and at term		Day 28 of life and term corrected age	No
Secondary	Retinopathy of prematurity (Worst grade)		Within hospitalization	No