Doxycycline Treatment to Prevent Progressive Coronary Artery Dilation in Children With Kawasaki Disease
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 25 children with KD and enlarged coronary arteries for two 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.
Drug: Standard care
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase 2 Study to Assess the Efficacy and Safety of Doxycycline in Preventing Coronary Artery Aneurysm Formation and Progression|
- Coronary artery diameter change [ Time Frame: 24 months ] [ Designated as safety issue: No ]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.
- Assess the change in MMP-9 level [ Time Frame: 24 months ] [ Designated as safety issue: No ]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 [ Time Frame: 24 months ] [ Designated as safety issue: No ]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).
|Study Start Date:||October 2013|
|Estimated Study Completion Date:||December 2018|
|Estimated Primary Completion Date:||August 2016 (Final data collection date for primary outcome measure)|
These patients will receive doxycycline at the acute phase of their disease
The interventional arm of the study will receive doxycycline 4.4 mg/kg/day for 14 days besides receiveing standard care: IVIG and/or Remicade.
Active Comparator: Standard care
The comparative arm of the study will receive standard care for Kawasaki disease, but not doxycycline
Drug: Standard care
Standard medical care will be provided to the comparative arm of the study administering IVIG and/or Remicade, but not doxycycline.
Other Name: IVIG and Remicade
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.
- 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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01917721
|Contact: Andras Bratincsak, Md PhDfirstname.lastname@example.org|
|United States, Hawaii|
|Kapiolani Medical Center for Women and Children||Recruiting|
|Honolulu, Hawaii, United States, 96826|
|Contact: Andras Bratincsak|
|Principal Investigator: Andras Bratincsak, MD PhD|
|Sub-Investigator: Marian Melish, MD|
|Principal Investigator:||Andras Bratincsak, MD PhD||Hawaii Pacific Health|