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Investigation in Myositis-associated Pneumonitis of Prednisolone And Concomitant Tacrolimus (IMPPACT)

Primary Purpose

Interstitial Pneumonitis, Polymyositis, Dermatomyositis

Status
Completed
Phase
Phase 2
Locations
Japan
Study Type
Interventional
Intervention
Tacrolimus
Sponsored by
Tokyo Medical and Dental University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Interstitial Pneumonitis focused on measuring Interstitial pneumonitis, Polymyositis, Dermatomyositis, Tacrolimus, Corticosteroids

Eligibility Criteria

16 Years - 74 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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
  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

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

  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

Sites / Locations

  • Hokkaido University Hospital
  • Tsukuba University Hospital
  • Osaka Minami Medical Center
  • Juntendo University Hospital
  • Tokyo Medical and Dental University Hospital
  • The University of Tokyo Hospital
  • Keio University Hospital
  • International Medical Center of Japan
  • Chiba University Hospital
  • Nagasaki University Hospital of Medicine and Dentistry
  • Tokushima University Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Prospective investigation group

Arm Description

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.

Outcomes

Primary Outcome Measures

Overall Survival
Overall survival (OS) was calculated from the day on which the protocol treatment was started until death due to any cause. Participants still alive were censored at the date they were last known to be alive.

Secondary Outcome Measures

Progression-free Survival
Patients were considered to have reached the progression if they died, or if they met all the following criteria; (1) ≥10% decline from baseline FVC or ≥15mmHg increase in baseline resting P(A-a)O2, (2) a worsening of interstitial pneumonitis findings by chest CT compared to the most recent study, confirmed by a radiologist, and (3) exclusion of pneumocystis pneumonia, cytomegalovirus pneumonia, and other pulmonary infection on clinical ground.

Full Information

First Posted
July 19, 2007
Last Updated
March 10, 2020
Sponsor
Tokyo Medical and Dental University
Collaborators
Japan Medical Association, Astellas Pharma Inc
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1. Study Identification

Unique Protocol Identification Number
NCT00504348
Brief Title
Investigation in Myositis-associated Pneumonitis of Prednisolone And Concomitant Tacrolimus
Acronym
IMPPACT
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
March 2020
Overall Recruitment Status
Completed
Study Start Date
July 2007 (undefined)
Primary Completion Date
January 2011 (Actual)
Study Completion Date
January 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Tokyo Medical and Dental University
Collaborators
Japan Medical Association, Astellas Pharma Inc

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Interstitial Pneumonitis, Polymyositis, Dermatomyositis
Keywords
Interstitial pneumonitis, Polymyositis, Dermatomyositis, Tacrolimus, Corticosteroids

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
25 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Prospective investigation group
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Tacrolimus
Other Intervention Name(s)
Prograf
Intervention Description
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.
Primary Outcome Measure Information:
Title
Overall Survival
Description
Overall survival (OS) was calculated from the day on which the protocol treatment was started until death due to any cause. Participants still alive were censored at the date they were last known to be alive.
Time Frame
52 weeks
Secondary Outcome Measure Information:
Title
Progression-free Survival
Description
Patients were considered to have reached the progression if they died, or if they met all the following criteria; (1) ≥10% decline from baseline FVC or ≥15mmHg increase in baseline resting P(A-a)O2, (2) a worsening of interstitial pneumonitis findings by chest CT compared to the most recent study, confirmed by a radiologist, and (3) exclusion of pneumocystis pneumonia, cytomegalovirus pneumonia, and other pulmonary infection on clinical ground.
Time Frame
52 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
16 Years
Maximum Age & Unit of Time
74 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Experimental treatment group 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 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) 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 16 to 74 years of age Historical control group 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 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) 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 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) 16 to 74 years of age Exclusion Criteria: Experimental treatment group 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 Use of immunosuppressive agents other than corticosteroids within 12 weeks (84 days) prior to the initiation of the study drug Could not exclude the following conditions on clinical ground: drug-induced pneumonitis, occupational lung disease, hypersensitivity pneumonitis, radiation-induced lung injury 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 Presence of pancreatitis Presence of diabetes mellitus with the exception of glucocorticoid-induced one that is well-controlled (HbA1c < 6.5%) Serum creatinine of 1.5 mg/dL or above 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 Serum potassium above the upper limit of normal Presence of ischemic heart disease, arrhythmia requiring treatment, congestive heart failure, or pulmonary hypertension requiring treatment Presence or history of malignancy with the exception of those without relapse off treatment for 5 years or longer Presence of serious active infection Presence of active hepatitis B, hepatitis C, or HIV infection History of severe drug hypersensitivity reaction 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 Participation in another clinical trial or post-marketing clinical study within 26 weeks (182 days) prior to screening 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 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 Could not exclude the following conditions on clinical ground: drug-induced pneumonitis, occupational lung disease, hypersensitivity pneumonitis, radiation-induced lung injury 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 Presence of pancreatitis Presence of diabetes mellitus with the exception of glucocorticoid-induced one that is well-controlled (HbA1c < 6.5%) Serum creatinine of 1.5 mg/dL or above 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 Serum potassium above the upper limit of normal Presence of ischemic heart disease, arrhythmia requiring treatment, congestive heart failure, or pulmonary hypertension requiring treatment Presence or history of malignancy with the exception of those without relapse off treatment for 5 years or longer Presence of serious active infection including active hepatitis B, hepatitis C, or HIV infection 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Nobuyuki Miyasaka, MD, PhD
Organizational Affiliation
Tokyo Medical and Dental University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Hokkaido University Hospital
City
Sapporo
State/Province
Hokkaido
ZIP/Postal Code
060-8648
Country
Japan
Facility Name
Tsukuba University Hospital
City
Tsukuba
State/Province
Ibaraki
ZIP/Postal Code
305-8576
Country
Japan
Facility Name
Osaka Minami Medical Center
City
Kawachi-Nagano
State/Province
Osaka
ZIP/Postal Code
586-8521
Country
Japan
Facility Name
Juntendo University Hospital
City
Bunkyo-ku
State/Province
Tokyo
ZIP/Postal Code
113-8431
Country
Japan
Facility Name
Tokyo Medical and Dental University Hospital
City
Bunkyo-ku
State/Province
Tokyo
ZIP/Postal Code
113-8519
Country
Japan
Facility Name
The University of Tokyo Hospital
City
Bunkyo-ku
State/Province
Tokyo
ZIP/Postal Code
113-8655
Country
Japan
Facility Name
Keio University Hospital
City
Shinjuku-ku
State/Province
Tokyo
ZIP/Postal Code
160-8582
Country
Japan
Facility Name
International Medical Center of Japan
City
Shinjuku-ku
State/Province
Tokyo
ZIP/Postal Code
162-8655
Country
Japan
Facility Name
Chiba University Hospital
City
Chiba
ZIP/Postal Code
260-8677
Country
Japan
Facility Name
Nagasaki University Hospital of Medicine and Dentistry
City
Nagasaki
ZIP/Postal Code
852-8501
Country
Japan
Facility Name
Tokushima University Hospital
City
Tokushima
ZIP/Postal Code
770-8503
Country
Japan

12. IPD Sharing Statement

Citations:
PubMed Identifier
31539061
Citation
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.
Results Reference
result
Links:
URL
https://academic.oup.com/rheumatology/advance-article/doi/10.1093/rheumatology/kez394/5572269
Description
Publisher's site

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Investigation in Myositis-associated Pneumonitis of Prednisolone And Concomitant Tacrolimus

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