Investigation in Myositis-associated Pneumonitis of Prednisolone And Concomitant Tacrolimus

NCT ID: NCT00504348

Last Updated: 2020-03-24

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 25 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-07-31
• Study Completion Date: 2011-01-31

Brief Summary

The purpose of the study is to evaluate the efficacy and safety of the combination treatment of tacrolimus and corticosteroid in polymyositis/dermatomyositis patients with interstitial pneumonitis with comparison against corticosteroid-treated historical controls.

Detailed Description

Interstitial pneumonia (IP) is a common complication of and has a significant impact on the prognosis of patients with polymyositis (PM) and dermatomyositis (DM). Reported prevalence of IP in PM/DM patients varies between 23 to 65% depending on criteria applied as well as on clinical settings of studied cohorts, and an earlier overview and a later study reported its high short-term mortality.

However, treatment for this grave complication has not yet been either established or even been prospectively investigated. Glucocorticoids, while long been considered as the first-line drugs, is effective in less than 50% of patients. Furthermore, the mortality of these glucocorticoids-resistant patients does not improve even if immunosuppressive drugs are later added.

Recently, we and others reported retrospective data which suggest that either an early addition of immunosuppressive drugs to glucocorticoids or the combined use of glucocorticoids and immunosuppressive drugs from the initial treatment may improve the survival of PM/DM patients. To save lives of PM/DM-IP patients, desperate treating physicians have started using this approach, strongly urging the conduct of prospective studies to investigate the superiority of this approach over glucocorticoids alone. At the same time, it was considered not ethically appropriate to conduct a prospective study with a concurrent controlled group receiving glucocorticoids alone given the presence of the PM/DM-IP subtype with rapidly progressive course and high short-term mortality if treated with glucocorticoids alone and the absence of useful demographic or bio-markers which could distinguish patients with this subtype early. Among immunosuppressive drugs used in the treatment of PM/DM-IP, tacrolimus has recently been suggested to be effective even for those patients who are resistant to cyclosporine or cyclosphosphamide.

To investigate whether the combined initial treatment of glucocorticoids and tacrolimus is superior to glucocorticoids alone in PM/DM-IP patients, we conducted a multicenter clinical trial to evaluate the efficacy and safety of a combination treatment of glucocorticoids and tacrolimus for 1 year in patients with newly developed active PM/DM-IP or its relapse by comparing against clinical outcome of historical control patients who were treated with glucocorticoid alone as an initial treatment.

Conditions

Interstitial Pneumonitis; Polymyositis; Dermatomyositis

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Prospective investigation group

Tacrolimus treatment is to be initiated at the starting dose of 0.075mg/kg/day, adjusted to maintain its whole blood trough levels between 5 and 10 ng/mL for 52 weeks. All patients are to receive glucocorticoids with the starting doses equivalent to between 0.6 and 1.0 mg/kg/day of prednisolone which are to be continued for the first 28 days after which be subsequently tapered according to a predefined guideline. Up to two courses of pulse intravenous glucocorticoid therapy are allowed during that period.

Group Type: EXPERIMENTAL

Tacrolimus

Intervention Type: DRUG

Start at the standard starting dose of 0.075mg/kg/day divided into two doses, then adjust doses based on clinical response and tolerability, but maintain whole blood trough levels between 5 to 10 ng/mL and total daily doses equal to or below 0.3mg/kg.

Interventions

Tacrolimus

Start at the standard starting dose of 0.075mg/kg/day divided into two doses, then adjust doses based on clinical response and tolerability, but maintain whole blood trough levels between 5 to 10 ng/mL and total daily doses equal to or below 0.3mg/kg.

Intervention Type: DRUG

Other Intervention Names

Prograf

Eligibility Criteria

Inclusion Criteria

Experimental treatment group

1. Diagnosis of definite or probable polymyositis or dermatomyositis by criteria of Bohan et al, or of clinically-amyopathic dermatomyositis by the definition proposed by Sontheimer et al

2. High-resolution CT findings consistent with interstitial pneumonitis, confirmed by a radiologist. If consolidation is the only abnormal findings, the patient must have pathologically documented evidence of interstitial pneumonitis of other histological type than cryptogenic organizing pneumonia/bronchiolitis obliterans organizing pneumonia (the patient could have more than one histological type including cryptogenic organizing pneumonia/bronchiolitis obliterans organizing pneumonia)

3. Meet two or more of the following criteria (must include 1) 1. Serum KL-6 above the upper normal limit 2. Presence of dyspnea on exertion (grade 2 on the Magnitude of Task component of the Mahler Modified Dyspnea Index 3. PaO2 of less than 80 mmHg while breathing ambient air at rest, not accompanied by abnormal increase of PaCO2 4. Vital capacity < 80% predicted, or diffusing capacity for carbon monoxide < 65% predicted 5. Meet at least one of the following condition over the 12-week period (84 days) prior to the initiation of the study drug

• Decrease in either % forced vital capacity or % diffusing capacity for carbon monoxide of 10% or more
• Worsening of interstitial pneumonitis findings by chest CT, confirmed by a radiologist

4. 16 to 74 years of age

Historical control group

1. Diagnosis of definite or probable polymyositis or dermatomyositis by criteria of Bohan et al, or of clinically-amyopathic dermatomyositis by the definition proposed by Sontheimer et al

2. High-resolution CT findings consistent with interstitial pneumonitis, confirmed by a radiologist. If consolidation is the only abnormal findings, the patient must have pathologically documented evidence of interstitial pneumonitis of other histological type than cryptogenic organizing pneumonia/bronchiolitis obliterans organizing pneumonia (the patient could have more than one histological type including cryptogenic organizing pneumonia/bronchiolitis obliterans organizing pneumonia)

3. Meet two or more of the following criteria (must include 1) 1. Serum KL-6 above the upper normal limit 2. Presence of dyspnea on exertion (grade 2 on the Magnitude of Task component of the Mahler Modified Dyspnea Index 3. PaO2 of less than 80 mmHg while breathing ambient air at rest, not accompanied by abnormal increase of PaCO2 4. Vital capacity < 80% predicted, or diffusing capacity for carbon monoxide < 65% predicted 5. Meet at least one of the following condition over the 12-week period (84 days) prior to the initiation of the study drug

• Decrease in either % forced vital capacity or % diffusing capacity for carbon monoxide of 10% or more
• Worsening of interstitial pneumonitis findings by chest CT, confirmed by a radiologist

5. 16 to 74 years of age

2. Could not exclude the following conditions on clinical ground: drug-induced pneumonitis, occupational lung disease, hypersensitivity pneumonitis, radiation-induced lung injury

3. Presence of end-stage interstitial pneumonitis as identified on the basis of a vital capacity < 45% predicted, diffusing capacity for carbon monoxide < 30% predicted, or lung CT with predominantly honeycombing appearance

4. Presence of pancreatitis

5. Presence of diabetes mellitus with the exception of glucocorticoid-induced one that is well-controlled (HbA1c < 6.5%)

6. Serum creatinine of 1.5 mg/dL or above

7. Presence of liver dysfunction (AST(GOT) or ALT (GPT) greater than 2.5 times the upper limit of normal) with the exception of the one that is considered to be due to myositis and is accompanied by the elevation of muscle enzymes above the upper limit of normal

8. Serum potassium above the upper limit of normal

9. Presence of ischemic heart disease, arrhythmia requiring treatment, congestive heart failure, or pulmonary hypertension requiring treatment

10. Presence or history of malignancy with the exception of those without relapse off treatment for 5 years or longer

11. Presence of serious active infection including active hepatitis B, hepatitis C, or HIV infection

12. Other medical condition which, in the investigator's judgment, may be associated with increased risk to the subject or may interfere with study assessments or outcomes

Exclusion Criteria

Experimental treatment group

1. Use of corticosteroids at doses equivalent to or higher than prednisolone 0.6mg/kg/day within 4 weeks (28 days) prior to the initiation of the study drug

2. Use of immunosuppressive agents other than corticosteroids within 12 weeks (84 days) prior to the initiation of the study drug

3. Could not exclude the following conditions on clinical ground: drug-induced pneumonitis, occupational lung disease, hypersensitivity pneumonitis, radiation-induced lung injury

4. Presence of end-stage interstitial pneumonitis as identified on the basis of a vital capacity < 45% predicted, diffusing capacity for carbon monoxide < 30% predicted, or lung CT with predominantly honeycombing appearance

5. Presence of pancreatitis

6. Presence of diabetes mellitus with the exception of glucocorticoid-induced one that is well-controlled (HbA1c < 6.5%)

7. Serum creatinine of 1.5 mg/dL or above

8. Presence of liver dysfunction (AST(GOT) or ALT (GPT) greater than 2.5 times the upper limit of normal) with the exception of the one that is considered to be due to myositis and is accompanied by the elevation of muscle enzymes above the upper limit of normal

9. Serum potassium above the upper limit of normal

10. Presence of ischemic heart disease, arrhythmia requiring treatment, congestive heart failure, or pulmonary hypertension requiring treatment

11. Presence or history of malignancy with the exception of those without relapse off treatment for 5 years or longer

12. Presence of serious active infection

13. Presence of active hepatitis B, hepatitis C, or HIV infection

14. History of severe drug hypersensitivity reaction

15. Patients who are pregnant or breast-feeding, or patients who intend to or whose spouses intend to conceive during the course of the study, including the follow-up period

16. Participation in another clinical trial or post-marketing clinical study within 26 weeks (182 days) prior to screening

17. Other medical condition which, in the investigator's judgment, may be associated with increased risk to the subject or may interfere with study assessments or outcomes

Historical control group

• Minimum Eligible Age: 16 Years
• Maximum Eligible Age: 74 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Japan Medical Association

INDUSTRY

Sponsor Role: collaborator

Astellas Pharma Inc

INDUSTRY

Sponsor Role: collaborator

Tokyo Medical and Dental University

OTHER

Sponsor Role: lead

Responsible Party

Kazuki Takada, MD

Professor, Institute of Education

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Nobuyuki Miyasaka, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Tokyo Medical and Dental University

Locations

Hokkaido University Hospital

Sapporo, Hokkaido, Japan

Tsukuba University Hospital

Tsukuba, Ibaraki, Japan

Osaka Minami Medical Center

Kawachi-Nagano, Osaka, Japan

Juntendo University Hospital

Bunkyo-ku, Tokyo, Japan

Tokyo Medical and Dental University Hospital

Bunkyo-ku, Tokyo, Japan

The University of Tokyo Hospital

Bunkyo-ku, Tokyo, Japan

Keio University Hospital

Shinjuku-ku, Tokyo, Japan

International Medical Center of Japan

Shinjuku-ku, Tokyo, Japan

Chiba University Hospital

Chiba, , Japan

Nagasaki University Hospital of Medicine and Dentistry

Nagasaki, , Japan

Tokushima University Hospital

Tokushima, , Japan

Countries

Japan

References

Takada K, Katada Y, Ito S, Hayashi T, Kishi J, Itoh K, Yamashita H, Hirakata M, Kawahata K, Kawakami A, Watanabe N, Atsumi T, Takasaki Y, Miyasaka N. Impact of adding tacrolimus to initial treatment of interstitial pneumonitis in polymyositis/dermatomyositis: a single-arm clinical trial. Rheumatology (Oxford). 2020 May 1;59(5):1084-1093. doi: 10.1093/rheumatology/kez394.

Reference Type: RESULT

PMID: 31539061 (View on PubMed)

Other Identifiers

IICT-FK506-01

Identifier Type: -

Identifier Source: org_study_id