Doxycycline Treatment to Prevent Progressive Coronary Artery Dilation in Children With Kawasaki Disease
| Status: | Recruiting |
|---|---|
| Conditions: | Cardiology, Endocrine |
| Therapuetic Areas: | Cardiology / Vascular Diseases, Endocrinology |
| Healthy: | No |
| Age Range: | Any - 18 |
| Updated: | 8/18/2018 |
| Start Date: | October 2013 |
| End Date: | November 2022 |
| Contact: | Andras Bratincsak, Md PhD |
| Email: | andrasb@kapiolani.org |
| Phone: | 808-942-7707 |
Phase 2 Study to Assess the Efficacy and Safety of Doxycycline in Preventing Coronary Artery Aneurysm Formation and Progression
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.
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.
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.
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.
Inclusion Criteria:
Treatment arm: Patients aged 1 month to 18 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 +3 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 +3 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.
We found this trial at
1
site
1319 Punahou St
Honolulu, Hawaii 96826
Honolulu, Hawaii 96826
(808) 983-6000
Principal Investigator: Andras Bratincsak, MD PhD
Kapiolani Medical Center for Women and Children Hawai‘i Pacific Health is an integrated health care...
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