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

Sponsor

Hawaii Pacific Health (Other)

Overall Status

Recruiting

CT.gov ID

NCT01917721

Collaborator

(none)

Enrollment

Location

Arms

109

Anticipated Duration (Months)

0.5

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Kawasaki Disease Coronary Aneurysm	Drug: Doxycycline Drug: Placebo	Phase 2

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

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.
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.
Measure the coronary artery diameters before and after doxycycline treatment in children with KD.
Compare coronary artery measurements of children receiving only standard therapy for KD (IVIG, infliximab) with children receiving standard therapy and doxycycline treatment.
Design a multi-center prospective randomized blinded placebo-controlled trial to assess the efficacy of doxycycline in preventing coronary artery dilation and aneurysm.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

50 participants

Allocation:

Randomized

Intervention Model:

Single Group Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Oct 1, 2013

Anticipated Primary Completion Date :

Nov 1, 2022

Anticipated Study Completion Date :

Nov 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Doxycycline These patients will receive doxycycline at the acute phase of their disease	Drug: Doxycycline The interventional arm of the study will receive doxycycline 4.4 mg/kg/day for 21 days besides receiveing standard care: IVIG and/or Remicade.
Active Comparator: Placebo The comparative arm of the study will receive standard care and placebo for Kawasaki disease, but not doxycycline	Drug: Placebo Standard medical care and placebo will be provided to the comparative arm of the study administering IVIG and/or Remicade, but not doxycycline. Other Names: IVIG and Remicade

Arm

Intervention/Treatment

Experimental: Doxycycline

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

Drug: Doxycycline

The interventional arm of the study will receive doxycycline 4.4 mg/kg/day for 21 days besides receiveing standard care: IVIG and/or Remicade.

Active Comparator: Placebo

The comparative arm of the study will receive standard care and placebo for Kawasaki disease, but not doxycycline

Drug: Placebo

Standard medical care and placebo will be provided to the comparative arm of the study administering IVIG and/or Remicade, but not doxycycline.

Other Names:

IVIG and Remicade

Outcome Measures

Primary Outcome Measures

Coronary artery diameter change [24 months]
We will assess the change (+ or -) of coronary artery diameter from the beginning of doxycycline administration to the end of doxycycline administration and for an additional 2 months beyond that.

Secondary Outcome Measures

Assess the change in MMP-9 level [24 months]
We will draw blood samples before, during and after the administration of doxycyline to assess the effect on MMP-9 (matrix metalloproteinase 9).
Assess a change in TIMP level [24 months]
We will draw blood samples before, during and after the administration of doxycyline to assess the effect on MMP-9 (matrix metalloproteinase 9) and TIMP (tissue inhibitor of matrix metalloproteinase).

Eligibility Criteria

Criteria

Ages Eligible for Study:

1 Month to 21 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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:

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