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To Compare the Efficacy of the Addition of Methotrexate (MTX) to Current Standard Acute Graft-versus-host Disease (GVHD) First-line Treatment With Corticosteroids (MTX-aGVHD)

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ClinicalTrials.gov Identifier: NCT03371667
Recruitment Status : Recruiting
First Posted : December 13, 2017
Last Update Posted : July 17, 2019
Sponsor:
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Brief Summary:

Phase III randomized double-blinded trial designed to compare the efficacy of the addition of MTX to current standard acute GVHD first-line treatment with corticosteroids. The protocol will use a novel endpoint for benchmarking interventions based on a composite primary endpoint of GVHD-free and corticosteroids-free survival.

The primary endpoint of the trial will be the assessment of a composite endpoint of graft-versus-host disease-free and corticosteroids-free survival at 12 months after randomization


Condition or disease Intervention/treatment Phase
Allogeneic Disease GVH - Graft Versus Host Reaction GVHD, Acute Stem Cell Transplant Complications Drug: Methotrexate Drug: Placebo Phase 3

Detailed Description:

This is a phase III randomized, multicenter, double blinded controlled study. Patients who develop clinically meaningful acute GVHD and who meet all other entry criteria will be randomized 1:1 to receive either corticosteroids and placebo ("standard of care", control arm) or the combination of low-dose MTX with corticosteroids as first-line therapy for acute GVHD (MTX; "experimental arm").

The primary analysis of this hypothesis generation study is to estimate the composite endpoint of GVHD-free and corticosteroids-free survival at 12 months after randomization in both treatment arms. In fact, it is more and more established that such composite endpoint is a clinically very relevant one because it represents ideal recovery from allo-SCT (Stem Cell transplantation) (at 1 year after acute GVHD diagnosis) and a measure of cure without ongoing morbidity.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 102 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Multi-center Randomized in Double-blinded Phase III Study Comparing Standard Care Therapy Alone Versus Corticosteroids and Low-dose Methotrexate (MTX) for the First-line Treatment of Acute Graft-versus-host Disease After Allogeneic Stem Cell Transplantation
Actual Study Start Date : August 16, 2018
Estimated Primary Completion Date : September 2021
Estimated Study Completion Date : September 2021


Arm Intervention/treatment
Experimental: Methotrexate
  • 5mg/Kg/day methotrexate for 4 weeks then 3 mg/m2 every two weeks for 12 weeks
  • 2mg/kg/day PO prednisone prednisone (or 1.6 mg/kg/day IV methylprednisolone) once daily.
  • 10 mg po or iv lederfolin after each MTX administration
Drug: Methotrexate

Methotrexate 5 mg/m2 will be given once week for 4 weeks, then 3 mg/m2 every two weeks for 12 weeks. Body surface area will be capped at 2 m2.

Methotrexate will be given as an IV infusion over 15 minutes. All patients will received prednisone 2 mg/kg.day PO (or methylprednisolone 1.6 mg/Kg/day) for 3 days.

For responding patients between day 4 and 28, the dose of prednisone must be at least 0.25 mg/kg/day prednisone (or 0.2 mg/kg/day methylprednisolone).

All patients should receive a folinic acid supplementation 24 hours after each MTX/placebo administration.

Lederfoldin 10 mg po or iv will be administered on days 2, 9, 16 and 23. Lederfoldin 10 mg po or iv will be administered on days 37, 51, 65, 79, 93 and 103.


Placebo Comparator: Placebo
  • Once a week placebo for 4 weeks then every two weeks for 12 weeks
  • 2 mg/kg/day PO prednisone (or 1.6 mg/kg/day IV methylprednisolone) once daily.
  • 10 mg po or iv lederfolin after each placebo administration
Drug: Placebo

Placebo 5 mg/m2 will be given once week for 4 weeks, then 3 mg/m2 every two weeks for 12 weeks. Body surface area will be capped at 2 m2.

Placebo will be given as an IV infusion over 15 minutes. All patients will received prednisone 2 mg/kg.day PO (or methylprednisolone 1.6 mg/Kg/day) for 3 days.

For responding patients between day 4 and 28, the dose of prednisone must be at least 0.25 mg/kg/day prednisone (or 0.2 mg/kg/day methylprednisolone).

All patients should receive a folinic acid supplementation 24 hours after each MTX/placebo administration.

Lederfoldin 10 mg po or iv will be administered on days 2, 9, 16 and 23. Lederfoldin 10 mg po or iv will be administered on days 37, 51, 65, 79, 93 and 103.





Primary Outcome Measures :
  1. Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization. [ Time Frame: Evaluation will be performed at time of inclusion ]
    GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.

  2. Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (1). [ Time Frame: Evaluation will be performed before start of MTX at the randomization. ]
    GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.

  3. Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (2). [ Time Frame: Evaluation will be performed at Day 8 ]
    GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.

  4. Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (3). [ Time Frame: Evaluation will be performed at Day 15 ]
    GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.

  5. Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (4). [ Time Frame: Evaluation will be performed at Day 22 ]
    GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.

  6. Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (5). [ Time Frame: Evaluation will be performed at Day 28 ]
    GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.

  7. Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (6). [ Time Frame: Evaluation will be performed at Day 36 ]
    GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.

  8. Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (7). [ Time Frame: Evaluation will be performed at Day 50 ]
    GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.

  9. Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (8). [ Time Frame: Evaluation will be performed at Day 56 ]
    GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.

  10. Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (9). [ Time Frame: Evaluation will be performed at Day 64 ]
    GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.

  11. Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (10) [ Time Frame: Evaluation will be performed at Day 78 ]
    GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.

  12. Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (11). [ Time Frame: Evaluation will be performed at Day 92 ]
    GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.

  13. Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (12). [ Time Frame: Evaluation will be performed at Day 102 ]
    GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.

  14. Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (13). [ Time Frame: Evaluation will be performed at 5 months after randomization. ]
    GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.

  15. Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (14). [ Time Frame: Evaluation will be performed at 6 months after randomization. ]
    GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.

  16. Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (17). [ Time Frame: Evaluation will be performed at 9 months after randomization . ]
    GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.

  17. Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (18). [ Time Frame: Evaluation will be performed at 12 months after randomization. ]
    GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.

  18. Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (19). [ Time Frame: Evaluation will be performed at time of inclusion. ]
    GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.

  19. Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (20). [ Time Frame: Evaluation will be performed before start of MTX at the randomization. ]
    GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.

  20. Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (21). [ Time Frame: Evaluation will be performed at Day 8. ]
    GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.

  21. Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (20). [ Time Frame: Evaluation will be performed at Day 15. ]
    GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.

  22. Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (21). [ Time Frame: Evaluation will be performed at Day 22. ]
    GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.

  23. Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (22). [ Time Frame: Evaluation will be performed at Day 28. ]
    GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.

  24. Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (23). [ Time Frame: Evaluation will be performed at Day 36 ]
    GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.

  25. Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (24). [ Time Frame: Evaluation will be performed at Day 50. ]
    GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.

  26. Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (25). [ Time Frame: Evaluation will be performed at Day 56. ]
    GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.

  27. Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (26). [ Time Frame: Evaluation will be performed at Day 64. ]
    GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.

  28. Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (27). [ Time Frame: Evaluation will be performed at Day 78. ]
    GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.

  29. Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (28). [ Time Frame: Evaluation will be performed at D92. ]
    GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.

  30. Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (29). [ Time Frame: Evaluation will be performed at Day 102. ]
    GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.

  31. Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (30). [ Time Frame: Evaluation will be performed at 5 months after randomization. ]
    GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.

  32. Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (31). [ Time Frame: Evaluation will be performed at 6 months after randomization. ]
    GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.

  33. Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (32). [ Time Frame: Evaluation will be performed at 9 months after randomization. ]
    GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.

  34. Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (33). [ Time Frame: Evaluation will be performed at 12 months after randomization. ]
    GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.


Secondary Outcome Measures :
  1. The incidence of severe adverse events within the first 12 months after randomization [ Time Frame: 12 months after randomization ]
  2. The proportion of complete remission (CR), very good partial response (VGPR), partial response (PR), mixed response (MR), no response (NR) and progression at day 28, day 56 and best response within the first 12 months after randomization. [ Time Frame: at day 28, day 56 and best response within the first 12 months after randomization. ]
  3. The proportion of GVHD flare within the first 12 months after randomization. [ Time Frame: 12 months after randomization ]
  4. Cumulative incidence of overall and severe chronic GVHD as assessed by NIH Consensus Criteria within the first 12 months after randomization(Jagasia, Greinix et al. 2015, Lee, Wolff et al. 2015). [ Time Frame: within the first 12 months after randomization ]
  5. Incidence of systemic of infection and CMV(cytomegalovirus ) reactivation within 3 months after randomization [ Time Frame: within 3 months after randomization ]
  6. Incidence of EBV (Epstein-Barr virus) reactivation and post-transplant lymphoproliferative disease within 12 months after randomization [ Time Frame: within 12 months after randomization ]
  7. Cumulative incidence of non-relapse mortality within the first 12 months after randomization. [ Time Frame: 12 months after randomization ]
  8. Corticosteroids-free, disease-free and overall survival within the first 12 months after randomization. [ Time Frame: 12 months after randomization ]
  9. Immune recovery and microbiota: number of patients with complete immune recovery (lymphocytes and dendritic cells) and correction of microbiota dysbiosis within the first 12 months [ Time Frame: 12 months after randomization ]
  10. Quality of Life (QoL)-1 [ Time Frame: 12 Months ]
    Evaluation by 1 questionnaire: EORTC QLQ-C30 (quality of life questionnaire) (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30)

  11. Quality of Life (QoL)-2 [ Time Frame: 12 Months ]
    Evaluation by 1 questionnaire: FACT-BMT (Functional Assessment of Cancer Therapy - Bone Marrow Transplant)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Adults patients (>=18 years old) with hematological diseases, who develop a first episode of acute GVHD (grade II-IV) requiring systemic therapy
  • First allo-SCT, with any type of donor, stem cell source, GVHD prophylaxis or conditioning regimen
  • Biopsy of acute GVHD target organ is recommended, but not required. Enrollment should not be delayed awaiting biopsy or pathology results
  • The patient must have received no previous systemic immune suppressive therapy for treatment of acute GVHD, except for a maximum 72 hours of prior corticosteroid therapy
  • Absolute neutrophil count (ANC) greater than 0.5 G/L
  • Platelets count greater than 20 G/L
  • Signed informed consent
  • Affiliation to a social security system (recipient or assign)
  • Women who are of childbearing potential must have a negative serum pregnancy test and agree to use a medically acceptable method of contraception until 6 months after the end of treatment.

Men with a partner of childbearing potential must agree to use a medically acceptable method of contraception until 6 months after the end of treatment.

Exclusion Criteria:

  • Hyper-acute GVHD as defined by the MD Anderson's criteria (Saliba, de Lima et al. 2007)
  • Flare of GVHD in a patient already on corticosteroid treatment
  • Overlap chronic GVHD as defined by the NIH Consensus Criteria (Jagasia, Greinix et al. 2015)
  • MTX given within 7 days of enrollment
  • Active uncontrolled infection
  • Relapsed/persistent malignancy requiring rapid immune suppression withdrawal
  • Acute GVHD after donor lymphocytes infusion (DLI)
  • Other systemic drugs for GVHD treatment (including extra-corporeal photopheresis)
  • If any prior steroid therapy (for indication other than GVHD), treatment at doses > 0.5 mg/kg/day methyl-prednisolone within 7 days prior to onset of acute GVHD
  • Patients who are pregnant, breast feeding, or if sexually active, unwilling to use effective birth control for the duration of the study
  • Patient on dialysis
  • Patients with veno-occlusive disease of the liver or with significant liver abnormalities who in the judgment of the treating physician cannot receive MTX
  • Patients requiring after inclusion in the protocol the continuation of one or more of the following medication: probenecide, trimethoprime (alone or in combination with sulfametoxazole), phenylbutazone or yellow fever vaccine
  • Patients with a history of intolerance/allergy to MTX
  • Hypersensitivity to the active substance or to any of the excipients

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03371667


Contacts
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Contact: Mohamad Mohty, PU-PH 01.49.28.26.20 mohamad.mohty@inserm.fr
Contact: Florent Malard, CCU-AH 01.49.28.26.20 malardf@yahoo.fr

Locations
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France
Saint Antoine Hospital - Hematology Department Recruiting
Paris, France, 75012
Contact: mohamad Mohty, PU-PH    01.49.28.26.20    mohamad.mohty@inserm.fr   
Contact: Florent Malard, CCU-AH    01.49.28.26.20    malardf@yahoo.fr   
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Investigators
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Principal Investigator: Mohamad Mohty, PU-PH Assistance Publique - Hôpitaux de Paris

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Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT03371667     History of Changes
Other Study ID Numbers: PHRC-K 16-150
2017-002691-98 ( EudraCT Number )
First Posted: December 13, 2017    Key Record Dates
Last Update Posted: July 17, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Assistance Publique - Hôpitaux de Paris:
Hematopoietic Stem Cell
Methotrexate
Corticosteroids therapy
Acute GVHD
Allogenic stem cell transplantation
Additional relevant MeSH terms:
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Graft vs Host Disease
Immune System Diseases
Prednisone
Methylprednisolone
Methylprednisolone Acetate
Methylprednisolone Hemisuccinate
Prednisolone
Prednisolone acetate
Methotrexate
Prednisolone hemisuccinate
Prednisolone phosphate
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents
Nucleic Acid Synthesis Inhibitors
Anti-Inflammatory Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists