Efficacy And Safety Of Clopidogrel In Neonates /Infants With Systemic To Pulmonary Artery Shunt Palliation (CLARINET)

International Randomized Double Blind Study Evaluating the Efficacy and the Safety of Clopidogrel 0.2 mg/kg Once Daily Versus Placebo in Neonates and Infants With Cyanotic Congenital Heart Disease Palliated With Systemic to Pulmonary Artery Shunt

Contemporary management of cyanotic congenital heart disease includes three stages of surgery. Incidence of shunt thrombosis and death between the two first stages of palliation remains important.

The primary objective of the study is to evaluate the efficacy of Clopidogrel 0.2 mg/kg/day for the reduction of all cause mortality and shunt related morbidity in neonates or infants with cyanotic congenital heart disease palliated with a systemic-to-pulmonary artery shunt (e.g. modified Blalock Taussig Shunt [BTS]).

The secondary objective was to assess the safety of Clopidogrel in the study population.

Study Overview

• Status: Completed
• Conditions: Heart Defects, Congenital
• Intervention / Treatment: Drug: placebo; Drug: Clopidogrel (SR25990)

Detailed Description

In this event-driven study, participants were to be randomized and treated as soon as possible after shunt placement. They were then to be treated and followed until the primary endpoint criteria was reached i.e. (shunt thrombosis, the next surgical procedure for correction of the congenital heart disease or death) or one year of age or the common study-end-date, which ever came first.

The common study-en-date was defined as the date when it was projected that 172 participants would have reached the primary endpoint criteria.

• Study Type: Interventional
• Enrollment (Actual): 906
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina
    • Sanofi-Aventis Administrative Office
• Belgium
  • Diegem, Belgium
    • Sanofi-Aventis Administrative Office
• Brazil
  • Sao Paulo, Brazil
    • Sanofi-Aventis Administrative Office
• Canada
  • Laval, Canada
    • Sanofi-Aventis Administrative Office
• China
  • Shangaï, China
    • Sanofi-Aventis Administrative Office
• Denmark
  • Horsholm, Denmark
    • Sanofi-Aventis Administrative Office
• Egypt
  • Cairo, Egypt
    • Sanofi-Aventis Administrative Office
• Finland
  • Helsinki, Finland
    • Sanofi-Aventis Administrative Office
• France
  • Paris, France
    • Sanofi-Aventis Administrative Office
• Germany
  • Berlin, Germany
    • Sanofi-Aventis Administrative Office
• Hong Kong
  • Causeway Bay, Hong Kong
    • Sanofi-Aventis Administrative Office
• Hungary
  • Budapest, Hungary
    • Sanofi-Aventis Administrative Office
• India
  • Mumbai, India
    • Sanofi-Aventis Administrative Office
• Israel
  • Natanya, Israel
    • Sanofi-Aventis Administrative Office
• Italy
  • Milano, Italy
    • Sanofi-Aventis Administrative Office
• Korea, Republic of
  • Seoul, Korea, Republic of
    • Sanofi-Aventis Administrative Office
• Malaysia
  • Kuala Lumpur, Malaysia
    • Sanofi-Aventis Administrative Office
• Mexico
  • Mexico, Mexico
    • Sanofi-Aventis Administrative Office
• Netherlands
  • Gouda, Netherlands
    • Sanofi-Aventis Administrative Office
• Norway
  • Lysaker, Norway
    • Sanofi-Aventis Administrative Office
• Poland
  • Warszawa, Poland
    • Sanofi-Aventis Administrative Office
• Portugal
  • Porto Salvo, Portugal
    • Sanofi-Aventis Administrative Office
• Russian Federation
  • Moscow, Russian Federation
    • Sanofi-Aventis Administrative Office
• Singapore
  • Singapore, Singapore
    • Sanofi-Aventis Administrative Office
• South Africa
  • Midrand, South Africa
    • Sanofi-Aventis Administrative Office
• Spain
  • Barcelona, Spain
    • Sanofi-Aventis Administrative Office
• Sweden
  • Bromma, Sweden
    • Sanofi-Aventis Administrative Office
• Taiwan
  • Taipei, Taiwan
    • Sanofi-Aventis Administrative Office
• Thailand
  • Bangkok, Thailand
    • Sanofi-Aventis Administraive Office
• United Kingdom
  • Guildford Surrey, United Kingdom
    • Sanofi-Aventis Admnistrative Office
• United States
  • New Jersey
    • Bridgewater, New Jersey, United States, 94609
      • Sanofi-Aventis Administrative Office

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 3 months (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Cyanotic congenital heart disease treated by any palliative systemic-to-pulmonary artery shunt.

Exclusion Criteria:

• Active bleeding or increase risk of bleeding,
• Allergy to 2 or more classes of drug,
• Unable to receive drug orally or enterically,
• Current clinically significant or persistent thrombocytopenia, neutropenia, severe hepatic or renal failure.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: placebo; Form: reconstituted solution using matching placebo powder Route: oral or enteric Frequency: once daily Dose: daily dose adjusted for weight
Experimental: Clopidogrel 0.2 mg/kg/day	Drug: Clopidogrel (SR25990); Form: reconstituted solution using Clopidogrel powder Route: oral or enteric Frequency: once daily Dose: daily dose adjusted for weight; Other Names: Plavix

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Reaching Primary Endpoint Criteria (First Occurrence of Death / Shunt Thrombosis / Cardiac Procedure < 120 Days Considered of Thrombotic Nature)	The primary endpoint was the first occurence of any of the following events: Death (including heart transplant); Shunt thrombosis requiring intervention; Hospitalization for bi-directional Glenn procedure or any cardiac related intervention prior to 120 days of age following an event or a shunt narrowing considered to be of thrombotic nature by the blinded adjudication committee. Only the first event was counted.	Median follow-up of 5.8 months (up to a maximum of 12 months after randomization)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Bleeding Events	Bleeding events spanning from signature of the Informed Consent Form up to the last visit were collected as for any Adverse Event. The 'on-treatment' period was defined as the period from randomization up until 28 days after treatment discontinuation or final follow-up visit, whichever came first, and participants who experienced bleeding events during that period were counted.	From randomization up to 28 days after treatment discontinuation or final follow-up visit, whichever comes first
Number of Participants According to Bleeding Type/Etiology	For all reported bleeding events, the type and the etiology of the bleeding event were collected. Participants who experienced bleeding events during the 'on-treatment period' were counted by bleeding type and etiology. Participants who had multiple bleedings could be counted several times.	From randomization up to 28 days after treatment discontinuation or final follow-up visit, whichever comes first

Collaborators and Investigators

• Sponsor: Sanofi
• Collaborators: Bristol-Myers Squibb
• Investigators: Study Director: International Clinical Development Clinical Study Director, Sanofi

Publications and helpful links

General Publications

• Wessel DL, Berger F, Li JS, Dahnert I, Rakhit A, Fontecave S, Newburger JW; CLARINET Investigators. Clopidogrel in infants with systemic-to-pulmonary-artery shunts. N Engl J Med. 2013 Jun 20;368(25):2377-84. doi: 10.1056/NEJMoa1114588.

Study record dates

Study Major Dates

• Study Start: November 1, 2006
• Primary Completion (Actual): February 1, 2010
• Study Completion (Actual): February 1, 2010

Study Registration Dates

• First Submitted: November 7, 2006
• First Submitted That Met QC Criteria: November 7, 2006
• First Posted (Estimate): November 8, 2006

Study Record Updates

• Last Update Posted (Estimate): October 24, 2014
• Last Update Submitted That Met QC Criteria: October 14, 2014
• Last Verified: October 1, 2014

More Information

Terms related to this study

• Keywords: clopidogrel; thrombosis; cyanotic congenital heart disease; shunt palliation
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Cardiovascular Abnormalities; Congenital Abnormalities; Heart Defects, Congenital; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Clopidogrel
• Other Study ID Numbers: EFC5314; 2006-000946-38 (EudraCT Number)