Doxycycline Treatment to Prevent Progressive Coronary Artery Dilation in Children With Kawasaki Disease

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Brief Title

Doxycycline Treatment to Prevent Progressive Coronary Artery Dilation in Children With Kawasaki Disease

Official Title

Phase 2 Study to Assess the Efficacy and Safety of Doxycycline in Preventing Coronary Artery Aneurysm Formation and Progression

Brief Summary

      Kawasaki disease (KD) affects infants and young children causing inflammation of the skin and
      blood vessels including the coronary arteries of the heart. Despite the currently available
      therapy, about one third of children develop enlargement of the coronary arteries that can
      lead to serious complications such as coronary artery stenosis, heart attack and even death.

      Kawasaki disease is the most common heart disease in children in the USA and it is especially
      common among the children of Hawaii. Every year, 50-90 children are diagnosed with KD in
      Hawaii and unfortunately there is no medication available to successfully prevent coronary
      artery damage in a subset of cases.

      During the first few weeks of the illness, cells of the immune system attack the coronary
      arteries and release a special substance (MMP) that is responsible for the coronary artery
      enlargement. There is a common antibiotic, doxycycline that can specifically block the action
      of this special substance (MMP). Research done on animals with KD showed that doxycycline was
      able to block this special substance and prevent enlargement of coronary arteries. Research
      in adults with enlargement of the main artery in their abdomen also showed that doxycycline
      may improve the outcome. Based on these studies doxycycline may be a promising therapy for
      children with KD, who develop enlargement of the coronary arteries.

      The investigators' proposed research study will assess the usefulness of doxycycline in
      preventing the progressive enlargement of coronary arteries in children with KD. The
      investigators plan to perform a small (pilot) study to evaluate how good is doxycycline in
      preventing coronary artery enlargement. The investigators will treat 50 children with KD and
      enlarged coronary arteries for three weeks with doxycycline and assess the change in coronary
      arteries as well as the blood levels of the special substance (MMP). If doxycycline proves to
      be beneficial in this small study, the investigators are going to design a large research
      study involving multiple institutions on Hawaii and the mainland and will recruit more
      children to be certain about the value of the proposed treatment. The investigators' proposal
      may change the treatment protocol of KD and could present a possible treatment for children
      with enlarged coronary arteries preventing potentially devastating consequences.
    

Detailed Description

      This research study attempts to reveal whether coronary artery dilation in patients with
      Kawasaki disease refractory to standard therapy could be prevented using a matrix
      metalloproteinase inhibitor: doxycycline.

      Hypothesis The investigators hypothesize that oral administration of doxycycline for two
      weeks during the acute phase of Kawasaki disease (KD) effectively blocks matrix
      metalloproteinase-9 (MMP-9) activity in the coronary arteries and therefore prevents the
      progression of coronary artery dilation and aneurysm formation in children with KD.

      Rationale There is no specific treatment for children with KD, who develop coronary artery
      dilation or aneurysm. Based on the animal studies and adult trials showing beneficial effect
      of doxycycline on coronary artery dilation and abdominal aneurysms, this selective MMP-9
      inhibitor offers a promising therapeutic strategy to prevent progressive coronary artery
      dilation in children with KD.

      Specific aims

        1. Measure serum MMP-9 activity, tissue inhibitor of metalloproteinase 1 activity (TIMP-1),
           serum levels of degradation products due to MMP-9 activity (elastin and gelatin
           degradation products) before and after treatment with doxycycline in children with KD.

        2. Compare serum MMP-9 activity and degradation product levels of children receiving only
           standard therapy for KD (IVIG, infliximab) with children receiving standard therapy and
           doxycycline treatment.

        3. Measure the coronary artery diameters before and after doxycycline treatment in children
           with KD.

        4. Compare coronary artery measurements of children receiving only standard therapy for KD
           (IVIG, infliximab) with children receiving standard therapy and doxycycline treatment.

        5. Design a multi-center prospective randomized blinded placebo-controlled trial to assess
           the efficacy of doxycycline in preventing coronary artery dilation and aneurysm.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Coronary artery diameter change

Secondary Outcome

 Assess the change in MMP-9 level

Condition

Kawasaki Disease

Intervention

Doxycycline

Study Arms / Comparison Groups

 Doxycycline
Description:  These patients will receive doxycycline at the acute phase of their disease

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

50

Start Date

October 2013

Completion Date

November 2022

Primary Completion Date

November 2022

Eligibility Criteria

        Inclusion Criteria:

        Treatment arm: Patients aged 1 month to 21 years with confirmed KD will be included in the
        study if they meet the following criteria:

          1. Patients with dilation of the right or left anterior descending coronary artery beyond
             a z-score of +2.5 during the acute febrile phase of KD.

          2. Patients with aneurysms of the right or left main coronary arteries during the acute
             febrile phase of KD.

          3. Patients with refractory KD after initial treatment with IVIG and dilated coronary
             arteries on an echocardiogram during the first month of KD.

        Comparison arm: Patients aged 1 month to 18 years with confirmed KD, who do not meet
        inclusion criteria to be included in the treatment group.

        1.Patients with right or left anterior descending coronary artery measurements below a
        z-score of +2.5 during the acute febrile phase of KD.

        Exclusion Criteria:

        The following patients will be excluded from this study:

          1. Patients with clinically incomplete KD.

          2. Patients whose parents refuse to administer doxycycline.

          3. Patients with acute renal failure.

          4. Patients with chronic liver and kidney disease.
      

Gender

All

Ages

1 Month - 21 Years

Accepts Healthy Volunteers

No

Contacts

Andras Bratincsak, MD PhD, 808-942-7707, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT01917721

Organization ID

2013-005


Responsible Party

Principal Investigator

Study Sponsor

Hawaii Pacific Health


Study Sponsor

Andras Bratincsak, MD PhD, Principal Investigator, Hawaii Pacific Health


Verification Date

August 2019