Clinical Trial Page

Summary
EudraCT Number:2004-004917-41
Sponsor's Protocol Code Number:WX17801
National Competent Authority:Portugal - INFARMED
Clinical Trial Type:EEA CTA
Trial Status:Completed
Date on which this record was first entered in the EudraCT database:2005-11-11
Trial results View results
A. Protocol Information
A.1Member State ConcernedPortugal - INFARMED
A.2EudraCT number2004-004917-41
A.3Full title of the trial
A prospective, randomized, double-blind, active controlled, parallel group, multi-center trial to assess the efficacy and safety of mycophenolate mofetil (MMF) in inducing response and maintaining remission in subjects with lupus nephritis.
A.3.2Name or abbreviated title of the trial where available
Aspreva Lupus Management Study (ALMS)
A.4.1Sponsor's protocol code numberWX17801
A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
A.8EMA Decision number of Paediatric Investigation Plan
B. Sponsor Information
B.Sponsor: 1
B.1.1Name of SponsorAspreva Pharmaceuticals Corporation as part of the Roche-Aspreva Collaboration Agreement
B.1.3.4CountryCanada
B.3.1 and B.3.2Status of the sponsorCommercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1Name of organisation providing support
B.4.2Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1Name of organisation
B.5.2Functional name of contact point
D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3IMP RoleTest
D.2 Status of the IMP to be used in the clinical trial
D.2.1IMP to be used in the trial has a marketing authorisation Information not present in EudraCT
D.2.1.1.1Trade name CellCept®
D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Limited UK
D.2.1.2Country which granted the Marketing AuthorisationPortugal
D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
D.2.5.1Orphan drug designation number
D.3 Description of the IMP
D.3.1Product nameMycophenolate mofetil
D.3.2Product code Ro 106-1443
D.3.4Pharmaceutical form Film-coated tablet
D.3.4.1Specific paediatric formulation Information not present in EudraCT
D.3.7Routes of administration for this IMPOral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8INN - Proposed INNMycophenolate mofetil
D.3.9.2Current sponsor codeRo 106-1443
D.3.10 Strength
D.3.10.1Concentration unit mg milligram(s)
D.3.10.2Concentration typeequal
D.3.10.3Concentration number500
D.3.11 The IMP contains an:
D.3.11.1Active substance of chemical origin Yes
D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
The IMP is a:
D.3.11.3Advanced Therapy IMP (ATIMP) Information not present in EudraCT
D.3.11.3.1Somatic cell therapy medicinal product No
D.3.11.3.2Gene therapy medical product No
D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
D.3.11.5Radiopharmaceutical medicinal product No
D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
D.3.11.7Plasma derived medicinal product Information not present in EudraCT
D.3.11.8Extractive medicinal product Information not present in EudraCT
D.3.11.9Recombinant medicinal product Information not present in EudraCT
D.3.11.10Medicinal product containing genetically modified organisms No
D.3.11.11Herbal medicinal product No
D.3.11.12Homeopathic medicinal product No
D.3.11.13Another type of medicinal product No
D.IMP: 2
D.1.2 and D.1.3IMP RoleTest
D.2 Status of the IMP to be used in the clinical trial
D.2.1IMP to be used in the trial has a marketing authorisation Information not present in EudraCT
D.2.1.1.1Trade name CellCept®
D.2.1.1.2Name of the Marketing Authorisation holderRoche Laboratories Inc., USA
D.2.1.2Country which granted the Marketing AuthorisationPuerto Rico
D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
D.2.5.1Orphan drug designation number
D.3 Description of the IMP
D.3.1Product nameMycophenolate mofetil
D.3.2Product code Ro 106-1443
D.3.4Pharmaceutical form Film-coated tablet
D.3.4.1Specific paediatric formulation Information not present in EudraCT
D.3.7Routes of administration for this IMPOral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8INN - Proposed INNMycophenolate mofetil
D.3.9.2Current sponsor codeRo 106-1443
D.3.10 Strength
D.3.10.1Concentration unit mg milligram(s)
D.3.10.2Concentration typeequal
D.3.10.3Concentration number500
D.3.11 The IMP contains an:
D.3.11.1Active substance of chemical origin Yes
D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
The IMP is a:
D.3.11.3Advanced Therapy IMP (ATIMP) Information not present in EudraCT
D.3.11.3.1Somatic cell therapy medicinal product No
D.3.11.3.2Gene therapy medical product No
D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
D.3.11.5Radiopharmaceutical medicinal product No
D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
D.3.11.7Plasma derived medicinal product Information not present in EudraCT
D.3.11.8Extractive medicinal product Information not present in EudraCT
D.3.11.9Recombinant medicinal product Information not present in EudraCT
D.3.11.10Medicinal product containing genetically modified organisms No
D.3.11.11Herbal medicinal product No
D.3.11.12Homeopathic medicinal product No
D.3.11.13Another type of medicinal product No
D.IMP: 3
D.1.2 and D.1.3IMP RoleComparator
D.2 Status of the IMP to be used in the clinical trial
D.2.1IMP to be used in the trial has a marketing authorisation Information not present in EudraCT
D.2.1.1.1Trade name Endoxan®
D.2.1.1.2Name of the Marketing Authorisation holderBaxter Oncology GmbH
D.2.1.2Country which granted the Marketing AuthorisationGermany
D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
D.2.5.1Orphan drug designation number
D.3 Description of the IMP
D.3.1Product nameEndoxan®
D.3.4Pharmaceutical form Powder for solution for infusion
D.3.4.1Specific paediatric formulation Information not present in EudraCT
D.3.7Routes of administration for this IMPIntravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8INN - Proposed INNcyclophosphamide
D.3.10 Strength
D.3.10.1Concentration unit g gram(s)
D.3.10.2Concentration typeequal
D.3.10.3Concentration number1
D.3.11 The IMP contains an:
D.3.11.1Active substance of chemical origin Yes
D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
The IMP is a:
D.3.11.3Advanced Therapy IMP (ATIMP) Information not present in EudraCT
D.3.11.3.1Somatic cell therapy medicinal product No
D.3.11.3.2Gene therapy medical product No
D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
D.3.11.5Radiopharmaceutical medicinal product No
D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
D.3.11.7Plasma derived medicinal product Information not present in EudraCT
D.3.11.8Extractive medicinal product Information not present in EudraCT
D.3.11.9Recombinant medicinal product Information not present in EudraCT
D.3.11.10Medicinal product containing genetically modified organisms No
D.3.11.11Herbal medicinal product No
D.3.11.12Homeopathic medicinal product No
D.3.11.13Another type of medicinal product No
D.IMP: 4
D.1.2 and D.1.3IMP RoleComparator
D.2 Status of the IMP to be used in the clinical trial
D.2.1IMP to be used in the trial has a marketing authorisation Information not present in EudraCT
D.2.1.1.1Trade name Imurel®
D.2.1.1.2Name of the Marketing Authorisation holderLaboratoire GlaxoSmithKline
D.2.1.2Country which granted the Marketing AuthorisationFrance
D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
D.2.5.1Orphan drug designation number
D.3 Description of the IMP
D.3.1Product nameImurel®
D.3.4Pharmaceutical form Capsule, hard
D.3.4.1Specific paediatric formulation Information not present in EudraCT
D.3.7Routes of administration for this IMPOral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8INN - Proposed INNAzathioprine
D.3.10 Strength
D.3.10.1Concentration unit mg milligram(s)
D.3.10.2Concentration typeequal
D.3.10.3Concentration number50
D.3.11 The IMP contains an:
D.3.11.1Active substance of chemical origin Yes
D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
The IMP is a:
D.3.11.3Advanced Therapy IMP (ATIMP) Information not present in EudraCT
D.3.11.3.1Somatic cell therapy medicinal product No
D.3.11.3.2Gene therapy medical product No
D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
D.3.11.5Radiopharmaceutical medicinal product No
D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
D.3.11.7Plasma derived medicinal product Information not present in EudraCT
D.3.11.8Extractive medicinal product Information not present in EudraCT
D.3.11.9Recombinant medicinal product Information not present in EudraCT
D.3.11.10Medicinal product containing genetically modified organisms No
D.3.11.11Herbal medicinal product No
D.3.11.12Homeopathic medicinal product No
D.3.11.13Another type of medicinal product No
D.8 Information on Placebo
D.8 Placebo: 1
D.8.1Is a Placebo used in this Trial?Yes
D.8.3Pharmaceutical form of the placeboFilm-coated tablet
D.8.4Route of administration of the placeboOral use
D.8 Placebo: 2
D.8.1Is a Placebo used in this Trial?Yes
D.8.3Pharmaceutical form of the placeboCapsule, hard
D.8.4Route of administration of the placeboOral use
E. General Information on the Trial
E.1 Medical condition or disease under investigation
E.1.1Medical condition(s) being investigated
Lupus Nephritis
MedDRA Classification
E.1.2 Medical condition or disease under investigation
E.1.2Version 4.1
E.1.2Level Low
E.1.2Classification code 10025140
E.1.3Condition being studied is a rare disease Yes
E.2 Objective of the trial
E.2.1Main objective of the trial
Primary Objective for Induction: To assess the efficacy of MMF compared to IVC for inducing response in subjects with lupus nephritis.

Primary Objective for Maintenance: To assess the long term efficacy of MMF compared to azathioprine in maintaining remission and renal function in subjects with lupus nephritis
E.2.2Secondary objectives of the trial
To assess other safety and efficacy parameters of MMF vs cyclophosphamide during induction therapy

To assess other safety and efficacy parameters of MMF vs azathioprine during maintenance therapy
E.2.3Trial contains a sub-study Information not present in EudraCT
E.3Principal inclusion criteria
1. Provision of written informed consent by subject or guardian, (with written assent for underage subjects)

2. Subject of either sex, 12 to 75 years of age (inclusive)

3. Diagnosis of SLE according to the American College of Rheumatology criteria (1997)

4. Kidney biopsy within the 6 months prior to first randomization with a histologic diagnosis of lupus nephritis (ISN/RPS 2003 classification of lupus nephritis) classes III, IV-S or IV-G, (A) or (A/C), or class V, alone or in combination with class III or IV. For biopsies reported according to ISDKC/WHO 1982 criteria, see Protocol Appendix 4

5. Laboratory evidence of active nephritis at screening, defined as:
Class IV-S or IV-G
•proteinuria ≥1000 mg/24 h or
•serum creatinine above 1.3 mg/dL (115 µmol/L) or
•active urinary sediment: any of >5 WBC/hpf, >5 RBC/hpf, 2+ or more on dipstick, or red cell casts in the absence of infection or other causes
Class III or V
•proteinuria ≥ 2000 mg/24 h or
•serum creatinine above 1.3 mg/dL (115 µmol/L)
E.4Principal exclusion criteria
1.Inability or unwillingness to provide written informed consent (and assent by underage subjects)

2. Inability or unwillingness to comply with the requirements of the protocol as determined by the investigator

3. In the opinion of the investigator, does not require long-term immunosuppressive treatment (in addition to corticosteroids)

4. Known hypersensitivity or contraindication to MMF, mycophenolic acid (MPA), cyclophosphamide, azathioprine (including known inherited TPMT deficiency), corticosteroids or any components of these drug products (e.g., allergy to Tween-80)

5. Pregnancy, nursing (breastfeeding) or use of a non-reliable method of contraception

6. Continuous dialysis starting more than 2 weeks before randomization into the induction phase and/or continuous dialysis with an anticipated duration of more than 8 weeks

7. Previous kidney transplant or planned transplant

8. Presence or history of:
•pancreatitis or GI hemorrhage within 6 months prior to first randomization
•active unhealed peptic ulcer within 3 months prior to first randomization. If an ulcer has healed and the subject is on adequate therapy, the subject may be randomized
•congenital or acquired immunodeficiency
•clinically significant drug or alcohol abuse
•malignancy within 5 years of first randomization, with the exception of basal cell carcinoma treated by complete excision
•lymphoproliferative disease or previous total lymphoid irradiation
•severe viral infection (CMV, HBV, HCV) within 3 months of first randomization; or known HIV infection

9. Other known clinically significant active medical conditions, such as:
•severe cardiovascular disease including CHF
•liver dysfunction [aspartate aminotransferase (AST), alanine aminotransferase (ALT), or bilirubin greater than 2.5 times the upper limit of normal] measured on at least 2 separate occasions
•COPD, or asthma requiring oral steroids
•bone marrow insufficiency unrelated to active SLE (according to investigator judgment) with white blood cell count (WBC) <2500/mm3; absolute neutrophil count (ANC) <1.3 x 103/μL; thrombocytopenia (platelet count) <50,000/mm3
•active bleeding disorders
•current infection requiring IV antibiotics

10. Any overlapping autoimmune condition for which the condition or treatment of the condition may affect the study assessments or outcomes (e.g., scleroderma with significant pulmonary hypertension; any condition for which additional immunosuppression is indicated). Overlapping conditions for which the condition or treatment is not expected to affect assessments or outcomes (e.g., Sjogren’s syndrome) are not excluded.

11. Other major physical or psychiatric illness or major traumatic injury within 6 months prior to first randomization

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

13.Participation in another clinical trial and/or receipt of investigational drugs within 4 weeks prior to screening visit

14. Use of medications prohibited prior to first randomization
E.5 End points
E.5.1Primary end point(s)
Induction phase:
The primary efficacy parameter for the induction phase is the number and percentage of subjects showing treatment response at 24 weeks, as adjudicated by the Clinical Endpoints Committee (CEC). Treatment response is defined as:
(a) Decrease in proteinuria, defined as decrease in the urine protein/creatinine ratio to <3 mg/mg in subjects with baseline nephrotic range proteinuria (≥3 mg/mg urine protein/creatinine ratio) or decrease in the urine protein/creatinine ratio by ≥50% in subjects with sub-nephrotic proteinuria (<3 mg/mg urine protein/creatinine ratio)
and
(b) Improvement in the baseline serum creatinine of ≥30% or stabilization of serum creatinine, i.e., a week 24 serum creatinine level ±25% of baseline

Maintenance phase:
The primary efficacy parameter is the time to treatment failure, as adjudicated by the CEC. A subject will be considered a treatment failure if he or she meets any of the following criteria:

1. Death

2. Chronic renal failure requiring chronic dialysis or renal transplant

3. Sustained doubling of serum creatinine concentration defined as the first serum creatinine value that is twice the mean of the lowest two values from screening to end of induction, as confirmed by a second serum creatinine value obtained at least 4 weeks after the initial doubling [modeled on Brenner et al., 2001]

4. Renal flare, defined as:
(a) proteinuric
•doubling of the urinary protein:creatinine ratio, and
•proteinuria ≥ 1 g/24 h in subjects with urinary protein ≤ 0.5 g/24 h at the end of the induction phase, or proteinuria ≥ 2 g/24 h in subjects with urinary protein > 0.5 g/24 h at the end of the induction phase

OR

(b) nephritic:
•25% increase in serum creatinine over the best value achieved from screening to end of induction.
Increase in creatinine must be accompanied by one or more of:
•simultaneous doubling of proteinuria reaching a minimum of 2 g/24 h (or ratio equivalent)
•new/increased hematuria (blood 2+ or more on dipstick)
•appearance of cellular casts.
To meet the definition of treatment failure, (a) or (b) must be confirmed by a second measurement 2 weeks later, in the absence of any change in ACE/ARB medication, use of NSAIDs/COX2 inhibitors, or intercurrent infection.

5. Major extra-renal flare [defined as a British Isles Lupus Assessment Group (BILAG) score category A in one organ (not kidney) or three organs with concurrent category B scores]

6. Requirement for pulse IV corticosteroids, PPE, IVIG, or non-protocol immunosuppressive therapy, to treat deterioration or exacerbation

Subjects withdrawn for any other reason or lost to follow-up will be considered treatment failures.

E.6 and E.7 Scope of the trial
E.6Scope of the trial
E.6.1Diagnosis No
E.6.2Prophylaxis No
E.6.3Therapy No
E.6.4Safety Yes
E.6.5Efficacy Yes
E.6.6Pharmacokinetic No
E.6.7Pharmacodynamic No
E.6.8Bioequivalence No
E.6.9Dose response No
E.6.10Pharmacogenetic Information not present in EudraCT
E.6.11Pharmacogenomic No
E.6.12Pharmacoeconomic No
E.6.13Others No
E.7Trial type and phase
E.7.1Human pharmacology (Phase I) No
E.7.1.1First administration to humans Information not present in EudraCT
E.7.1.2Bioequivalence study Information not present in EudraCT
E.7.1.3Other Information not present in EudraCT
E.7.1.3.1Other trial type description
E.7.2Therapeutic exploratory (Phase II) No
E.7.3Therapeutic confirmatory (Phase III) Yes
E.7.4Therapeutic use (Phase IV) No
E.8 Design of the trial
E.8.1Controlled Yes
E.8.1.1Randomised Yes
E.8.1.2Open Yes
E.8.1.3Single blind No
E.8.1.4Double blind Yes
E.8.1.5Parallel group Yes
E.8.1.6Cross over Yes
E.8.1.7Other Yes
E.8.1.7.1Other trial design description
2-phase study: induction phase is open lable; maintenance phase is double blind
E.8.2 Comparator of controlled trial
E.8.2.1Other medicinal product(s) Yes
E.8.2.2Placebo Yes
E.8.2.3Other No
E.8.3 The trial involves single site in the Member State concerned No
E.8.4 The trial involves multiple sites in the Member State concerned Yes
E.8.5The trial involves multiple Member States Yes
E.8.6 Trial involving sites outside the EEA
E.8.6.1Trial being conducted both within and outside the EEA Yes
E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
E.8.7Trial has a data monitoring committee Information not present in EudraCT
E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
Until 144 treatment failures have been observed, or until the last subject has been followed for 36 months, whichever is earlier.
E.8.9 Initial estimate of the duration of the trial
E.8.9.1In the Member State concerned years4
E.8.9.1In the Member State concerned months5
E.8.9.1In the Member State concerned days
E.8.9.2In all countries concerned by the trial years4
E.8.9.2In all countries concerned by the trial months5
F. Population of Trial Subjects
F.1 Age Range
F.1.1Trial has subjects under 18 Yes
F.1.1.1In Utero No
F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
F.1.1.3Newborns (0-27 days) No
F.1.1.4Infants and toddlers (28 days-23 months) No
F.1.1.5Children (2-11years) No
F.1.1.6Adolescents (12-17 years) Yes
F.1.2Adults (18-64 years) Yes
F.1.3Elderly (>=65 years) Yes
F.2 Gender
F.2.1Female Yes
F.2.2Male Yes
F.3 Group of trial subjects
F.3.1Healthy volunteers No
F.3.2Patients Yes
F.3.3Specific vulnerable populations Information not present in EudraCT
F.3.3.1Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2005-11-11. Yes
F.3.3.2Women of child-bearing potential using contraception Information not present in EudraCT
F.3.3.3Pregnant women No
F.3.3.4Nursing women No
F.3.3.5Emergency situation No
F.3.3.6Subjects incapable of giving consent personally No
F.3.3.7Others No
F.4 Planned number of subjects to be included
F.4.1In the member state21
F.4.2 For a multinational trial
F.4.2.1In the EEA 195
F.4.2.2In the whole clinical trial 358
G. Investigator Networks to be involved in the Trial
N. Review by the Competent Authority or Ethics Committee in the country concerned
N.Competent Authority Decision Authorised
N.Date of Competent Authority Decision2005-12-29
N.Ethics Committee Opinion of the trial applicationFavourable
N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
N.Date of Ethics Committee Opinion2005-11-07
P. End of Trial
P.End of Trial StatusCompleted
P.Date of the global end of the trial2010-03-24
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