Mycophenolate Mofetil in Systemic Sclerosis

This study has been completed.
Sponsor:
Collaborator:
Aspreva Pharmaceuticals
Information provided by:
Boston University
ClinicalTrials.gov Identifier:
NCT00433186
First received: February 7, 2007
Last updated: March 29, 2011
Last verified: March 2011
  Purpose

This is a research study of an investigational product called Mycophenolate mofetil (MMF). The study is designed to establish the safety and potential benefit of MMF. MMF has proven one of the most effective medications to date for SLE and associated nephritis. It also appears to be active in polymyositis and dermatomyositis. This medication inhibits inosine monophosphate dehydrogenase, the rate-limiting enzyme in synthesis of guanosine nucleotides. It blocks the type II isoform found in activated lymphocytes more potently than the type I isoform inhibiting both T- and B-lymphocytes. In SSc, MMF has been tried after anti-thymocyte globulin in one small open label study with efficacy with a significant improvement in skin score. We will test the safety and efficacy of MMF in SSc. All study patients will receive the study medication. The effect of the study medication will be examined in two subgroups of patients: those with early or progressive skin disease (skin substudy) and those with muscle disease (muscle substudy). The change in modified Rodnan skin score (MRSS) and creatinine phosphokinase (CK) for, respectively, the skin and muscle substudies at 6 months after treatment will be compared to baseline values.


Condition Intervention Phase
Diffuse Cutaneous Systemic Sclerosis
Drug: Mycophenolate Mofetil
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I, Open-label Study of Mycophenolate Mofetil In Systemic Sclerosis

Resource links provided by NLM:


Further study details as provided by Boston University:

Primary Outcome Measures:
  • Skin Study: The primary evaluation of response will be improvement of the modified Rodnan skin score @ 6 months. Improvement of skin score, correlates with improvement in joint function, functional status and physician's global assessment. [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • Muscle Sub Study:The primary evaluation of response will be the CK at 6 months compared to baseline.Improvement after 6 months of tx compared to baseline CK will suggest efficacy [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • Safety evaluation. [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Secondary evaluations of response. Scleroderma Health Assessment Questionnaire (SHAQ): The SHAQ will be evaluated at study entry compared to 6 and 12 months. [ Time Frame: 6 months ] [ Designated as safety issue: No ]

Estimated Enrollment: 30
Study Start Date: March 2006
Study Completion Date: March 2011
Primary Completion Date: March 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: A
Mycophenolate
Drug: Mycophenolate Mofetil
Mycophenolate 3000 mg each day
Other Name: Cellcept

Detailed Description:

Systemic sclerosis (SSc) is an autoimmune/connective tissue disease with complex pathogenesis involving immune system dysregulation, leading to fibrosis. Inflammatory and autoimmune aspects of this disease overlap systemic lupus erythematosus (SLE), a disease shown clearly to respond to MMF. Activated T-cells, the probable target of MMF in SLE, likely also play an important role in SSc pathogenesis. Evidence for this includes the similarity of SSc skin disease to chronic graft versus host disease, a disease in which T-cells play a critical role. MMF has proven one of the most effective medications to date for SLE and associated nephritis [1]. It also appears to be active in polymyositis and dermatomyositis, disease that also show significant overlap with SSc [2]. Myositis can also be a feature of SSc, suggesting that his disease manifestation might be particularly likely to respond to MMF. MMF inhibits inosine monophosphate dehydrogenase, the rate-limiting enzyme in synthesis of guanosine nucleotides. It blocks the type II isoform found in activated lymphocytes more potently than the type I isoform inhibiting both T- and B-lymphocytes [3]. In SSc, mycophenolate has been tried after anti-thymocyte globulin in one small open label study with efficacy with a significant improvement in skin score [4]. However, MMF has not been tried alone inSSc and has not been tried in muscle disease associated with SSc. In this study, we will test the safety and efficacy of MMF in SSc. In this study all study patients will receive the medication.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Must meet the American College of Rheumatology criteria for systemic sclerosis with diffuse cutaneous disease or muscle involvement
  • Patients must also meet one of the following criteria:

SKIN SUBSTUDY (20 patients)

  • Be within 1 1/2 years of first non-Raynaud's disease manifestation.
  • How progression of skin disease at some time over the past 6 months prior to study entry based on either documented increase in skin score or new areas of skin involvement or progression (no more than 10 patients total recruited)

OR, MUSCLE SUBSTUDY (10 patients)

  • Have a serum creatinine phosphokinase (CK) greater than 2 times the upper limit of normal

    • Patients entering the study on the basis of elevated CK must also have subjective and/or objective weakness; clinical evidence of cardiac, pulmonary or gastrointestinal disease as a complication of the patient¿s systemic sclerosis; or progressive skin disease.
    • The total number of patients entered in criteria 2a and 2b (skin substudy) will be 20. Patients meeting both criteria 2c. and either 2a or 2b will first be recruited into the muscle substudy (by criteria 2c) until 10 patients have been recruited.
    • Male or female patients >18 years of age.
    • Able and willing to give written informed consent and comply with the requirements of the study protocol
    • Men and women of reproductive potential must agree to use an acceptable method of birth control during treatment and for 6 weeks after completion of treatment.
    • Adequate renal function as indicated by Cr less than or equal to 3.0
    • Adequate liver function, as indicated by SGOT and SGPT less than 2.5 times the upper limit of normal.
    • Negative serum pregnancy test (for women of child bearing age)

Exclusion Criteria:

  • Treatment with any investigational agent within 4 weeks of screening or 5 half-lives of the investigational drug (whichever is longer).
  • Ongoing use of high dose steroids (>10mg/day) or unstable steroid dose in the past 4 weeks.
  • Receipt of a live vaccine within 4 weeks prior to randomization.
  • Previous Treatment with MMF
  • Treatment with immunosuppressive, cytotoxic or anti-fibrotic drug within 4 weeks of screening other than anti-malarial. This includes cyclophosphamide, azathioprine (Immuran), methotrexate or other immunosuppressive or cytotoxic medication.
  • Treatment with cholestyramine within 1 week of trial entry.
  • History of HIV, Hepatitis B and/or Hepatitis C, or evidence of Hepatitis B or C at screening.
  • Moderate to severe hepatic impairment, Child-Pugh Class B or C.
  • History of recurrent significant infection or history of recurrent bacterial infections.
  • Known active bacterial, viral fungal mycobacterial, or other infection (including tuberculosis or atypical mycobacterial disease, but excluding fungal infections of nail beds) or any major episode of infection requiring hospitalization or treatment with i.v. antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks prior to screening.
  • Active gastrointestinal bleeding within 4 weeks of study entry or active serious gastrointestinal disease.
  • Pregnancy (a negative serum pregnancy test will be performed for all women of childbearing potential within 14 days of treatment).
  • Concomitant malignancies or previous malignancies within the last five years, with the exception of adequately treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix.
  • A history of phenylketonuria, hereditary deficiency of hypoxanthine-guanine phosphoribosyl-transferase, Lesch-Nyhan or Kelley-Seegmiller syndrome
  • Allergy to polysorbate 80/Tween
  • Subjects who are breastfeeding
  • Moderately severe renal dysfunction as indicated by Cr >3.0, dipstick protein >3+, or patient on dialysis.
  • Hemoglobin: < 8.5 gm/dL
  • Platelets: < 100,000/mm
  • AST or ALT >2.5 x Upper limit of normal unless related to muscle disease.
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00433186

Locations
United States, Massachusetts
Boston University School of Medicine
Boston, Massachusetts, United States, 02118
Sponsors and Collaborators
Boston University
Aspreva Pharmaceuticals
Investigators
Principal Investigator: Robert Lafyatis, MD Boston University School od Medicine Rheumatology Section
  More Information

No publications provided

Responsible Party: Robert Lafyatis, MD, Boston University Medical Center
ClinicalTrials.gov Identifier: NCT00433186     History of Changes
Other Study ID Numbers: H-25973
Study First Received: February 7, 2007
Last Updated: March 29, 2011
Health Authority: United States: Institutional Review Board

Keywords provided by Boston University:
Scleroderma

Additional relevant MeSH terms:
Scleroderma, Systemic
Scleroderma, Diffuse
Sclerosis
Connective Tissue Diseases
Skin Diseases
Pathologic Processes
Mycophenolate mofetil
Mycophenolic Acid
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antibiotics, Antineoplastic
Antineoplastic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on July 31, 2014