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

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 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.

Study Overview

• Status: Unknown
• Conditions: Kawasaki Disease; Coronary Aneurysm
• Intervention / Treatment: Drug: Doxycycline; Drug: Placebo

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 Type: Interventional
• Enrollment (Anticipated): 50
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Andras Bratincsak, Md PhD; Phone Number: 808-942-7707; Email: andrasb@kapiolani.org

Study Locations

• United States
  • Hawaii
    • Honolulu, Hawaii, United States, 96826
      • Recruiting
      • Kapiolani Medical Center for Women and Children
      • Contact: Andras Bratincsak
      • Principal Investigator: Andras Bratincsak, MD PhD
      • Sub-Investigator: Marian Melish, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 month to 21 years (ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Coronary artery diameter change	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.	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assess the change in MMP-9 level	We will draw blood samples before, during and after the administration of doxycyline to assess the effect on MMP-9 (matrix metalloproteinase 9).	24 months
Assess a change in TIMP level	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).	24 months

Collaborators and Investigators

• Sponsor: Hawaii Pacific Health
• Investigators: Principal Investigator: Andras Bratincsak, MD PhD, Hawaii Pacific Health

Publications and helpful links

General Publications

• Bratincsak A, Limm-Chan BN, Nerurkar VR, Ching LL, Reddy VD, Lim E, Shohet RV, Melish ME. Study design and rationale to assess Doxycycline Efficacy in preventing coronary Artery Lesions in children with Kawasaki disease (DEAL trial) - A phase II clinical trial. Contemp Clin Trials. 2018 Feb;65:33-38. doi: 10.1016/j.cct.2017.11.014. Epub 2017 Dec 5.

Study record dates

Study Major Dates

• Study Start (ACTUAL): October 1, 2013
• Primary Completion (ANTICIPATED): November 1, 2022
• Study Completion (ANTICIPATED): November 1, 2022

Study Registration Dates

• First Submitted: April 26, 2013
• First Submitted That Met QC Criteria: August 5, 2013
• First Posted (ESTIMATE): August 7, 2013

Study Record Updates

• Last Update Posted (ACTUAL): August 28, 2019
• Last Update Submitted That Met QC Criteria: August 26, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Keywords: doxycycline; coronary artery aneurysm; Kawasaki disease
• Additional Relevant MeSH Terms: Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Skin Diseases; Lymphatic Diseases; Vasculitis; Skin Diseases, Vascular; Coronary Disease; Aneurysm; Mucocutaneous Lymph Node Syndrome; Coronary Aneurysm; Anti-Infective Agents; Anti-Bacterial Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Doxycycline
• Other Study ID Numbers: 2013-005

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO