An open-label clinical trial of the combination treatment of tacrolimus and corticosteroid in polymyositis/dermatomyositis patients with interstitial pneumonitis, with comparison against corticosteroid-treated historical controls (IMPPACT)
Investigation in Myositis-associated Pneumonitis of Prednisolone And Concomitant Tacrolimus
25
Published manuscript reference
Published manuscript reference
The 52-week survival rate with the combination treatment (N= 26) was 88.0% (95% CI, 67.3, 96.0). Safety profiles of the combination treatment were consistent with those known for tacrolimus and high-dose glucocorticoids individually. Serious adverse events occurred in 11 patients (44.0%), which included four opportunistic infections. Only 16 patients, including only 1 deceased patient, were registered as historical controls, which precluded meaningful comparative analysis against the clinical trial patients. Our study provided findings which suggest that initial treatment with tacrolimus and glucocorticoids may improve short-term mortality of polymyositis/dermatomyositis-interstitial pneumonia patients with manageable safety profiles. This was the first prospective clinical investigation conducted according to the Good Clinical Practice Guideline of the International Conference on Harmonization for the treatment of this potentially life-threatening disease.
Kazuki Takada
Tokyo Medical and Dental University Hospital
1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519
+81-3-3813-6111
takada.rheu@tmd.ac.jp
Kazuki Takada
Tokyo Medical and Dental University Hospital
1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519
+81-3-3813-6111
takada.rheu@tmd.ac.jp
COMPLETED
July. 20, 2007
20
Interventional
Controlled trial with non-concurrent comparative group
2-3
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 hitological 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 hitological 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) Use of corticosteroids at doses equivalent to between 0.6 to 1.0mg/kg/day of prednisolone for 14 days or longer to treat interstitial pneumonitis on or after the day when the inclusion criteria (3) was met (up to two courses of pulse IV corticosteroid therapy within the first 28 days are allowed)
(5) 16 to 74 years of age
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
(1) Use of immunosuppressive agents other than corticosteroids within 12 weeks (84 days) prior to or 2 weeks (14 days) after the corticosteroid treatment as defined by the inclusion criteria (4) is initiated
(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
16age old over
75age old not
Both
Interstitial pneumonitis associated with polymyositis/dermatomyositis
Intervention type:DRUG
Name of intervention:Tacrolimus
Dose form / Japanese Medical Device Nomenclature:CAPSULE
Route of administration / Site of application:ORAL
Dose per administration:
0.0375-0.15
mg/kg
Dosing frequency / Frequency of use:BID
Planned duration of intervention:52 weeks
Intended dose regimen: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.
detailes of teratment arms:
Comparative intervention name:
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Overall survival
Progression-free survival
IMPPACT study central office
Hokkaido University Hospital, Tsukuba University Hospital, Chiba University Hospital, The University of Tokyo Hospital, Tokyo Medical and Dental University Hospital, International Medical Center of Japan, Juntendo University Hospital, Keio University Hospital, Osaka Minami Medical Center, Tokushima University Hospital, Nagasaki University Hospital of Medicine and Dentistry
Japan Medical Association
Astellas Pharma Inc.
Juntendo University Hospital, The Medical Department Ethics Committee
