1. What is Kawasaki disease?

Kawasaki disease is a vasculitic syndrome of unknown cause that occurs most often during childhood. It was first reported by Dr. Tomisaku Kawasaki in 1967. If untreated, about 25% of patients develop coronary arterial sequelae; however, the development of high-dose immunoglobulin therapy (Explanation) has decreased the incidence of such sequelae. Still, Kawasaki disease remains the most common cause of acquired heart disease in developed countries - over 1000 patients develop coronary arterial lesions each year in Japan alone. Therefore, there is an urgent need for new treatments.

2. What is the RAISE Study?

The RAISE Study is a multicenter, randomized, controlled trial to assess the efficacy of initial high-dose immunoglobulin plus prednisolone combination therapy. RAISE is an acronym for Randomized Controlled Trial to Assess Immunoglobulin Plus Steroid Efficacy for Kawasaki Disease.

3. What is the design of the study?

It is a prospective, randomized, controlled study. Participants in the treatment group will be treated with initial high-dose immunoglobulin plus prednisolone combination therapy. Those in the control group will receive high-dose immunoglobulin therapy, which is currently approved by the Ministry of Health, Labour and Welfare. Patients who fulfill the selection criteria will be randomly allocated to one of these groups at the Allocation Center.

4. What are the UMIN ID and password?

The UMIN ID is an ID necessary for receiving the services provided by the University Medical Information Network, or UMIN. Researchers who take part in the RAISE Study will be given 1 UMIN ID and 2 UMIN passwords. One password is for receiving UMIN's general services (eg, email and registering academic society meeting presentation titles). You will also need this password to access web pages restricted to RAISE Study researchers. The other password is used for the Internet Data Center, and is called the UMIN INDICE password. You need this password to register patients with the RAISE Study.

If you already have a UMIN ID, you can continue using that ID, as well as the UMIN general services password. However, you must obtain a new UMIN INDICE password, which is issued by the RAISE Study Secretariat and UMIN.

5. Tell us about the RAISE Study's website.

There are 2 areas in the RAISE Study's website.
(1) An area for participating researchers
Access is restricted: a UMIN ID and password for general services are required
(2) The patient registration and allocation page
Access is restricted: a UMIN ID and UMIN INDICE password are required. Because the URL is not disclosed to the general public, you must access the website for participating researchers shown in (1), and follow the link to the patient registration page.

6. How was the definition of severe Kawasaki disease determined?

Severe Kawasaki disease was defined by using the database of hospitals affiliated with Gunma University and using the risk scores created from the 750 patients who underwent high-dose immunoglobulin therapy (Kobayashi, T. et al., Circulation 113: 2606-2612, 2006). If severe Kawasaki disease is defined as a score of 5 points or higher, about 30% of Kawasaki disease patients have severe disease.

7. Won't patients who were assigned to the control group be at an unfair disadvantage to the group receiving initial high-dose immunoglobulin plus prednisolone combination therapy?

High-dose immunoglobulin plus prednisolone combination therapy is not a proven treatment, ie, there is as yet no conclusive evidence that initial high-dose immunoglobulin plus prednisolone combination therapy is effective for severe Kawasaki disease. Our study attempts to rigorously examine whether this regimen is indeed effective for severe Kawasaki disease. Because of the lack of conclusive findings, there is also no evidence indicating that the control group suffers a disadvantage.

8. Is prednisolone safe?

The safety of prednisolone for Kawasaki disease patients is not guaranteed. A study conducted in Gunma revealed the following side reactions among patients who underwent initial high-dose immunoglobulin plus prednisolone combination therapy:
1. Temporary appetite increase and obesity (moon-shaped face)
2. Temporary hypercholesterolemia
3. Temporary lymphocyte increase associated with neutropenia with a left shift
4. Infections (among 124 subjects, 2 suffered urinary tract infections and 3 developed viral infections.)
5. Temporary inability to sit (1 subject)
All patients had rapid improvement in symptoms, with no sequelae.

9. Why isn't methylprednisolone pulse therapy used as a method of administering steroids?

A US clinical study already examined the efficacy of high-dose immunoglobulin plus methylprednisolone pulse therapy as initial treatment. The results indicated that this combination therapy, when used as initial treatment, was not clinically superior to high-dose immunoglobulin therapy. Because of this, we chose not to include methylprednisolone pulse therapy as a method of administering steroids as initial treatment.

10. What additional therapies can be administered to patients who are unresponsive to treatment?

For additional treatment of refractory patients, please use the 2003 guidelines of the Japanese Society of Pediatric Cardiology and Cardiac Surgery as a reference, and provide treatment in line with the protocol your institution indicated when it registered with the RAISE Study. After the start of the present study, if your institution decides to change its protocol regarding the treatment of refractory patients, please contact the RAISE Study Secretariat.

11. Why is it necessary to record echocardiography findings on video?

In this study, the treatment method will be known by the chief physician responsible for providing treatment and by the patients. In such a case, there is a concern that the individuals who assess the echocardiograms may be biased in their interpretation of the image data. To eliminate the possibility of bias by measuring specialists who are not blinded to the treatment method, our design calls for a third person with no knowledge of the treatment method to make the final assessment regarding the presence of coronary lesions (the PROBE method). The RAISE Study Secretariat will edit the echocardiographic findings, so that echocardiographic images are shown continuously from start to finish.