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Clinical Study Comparing the New Immunosuppressive Drug Gusperimus With the Conventional Treatment in Wegener's Granulomatosis (SPARROW)

Primary Purpose

Wegeners Granulomatosis

Status
Terminated
Phase
Phase 3
Locations
Czech Republic
Study Type
Interventional
Intervention
Gusperimus + glucocorticoids
cyclophosphamide followed by methotrexate (azathioprine) + glucocorticoids or methotrexate (azathioprine) + glucocorticoids
Sponsored by
Nordic Pharma SAS
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Wegeners Granulomatosis focused on measuring gusperimus, Wegeners granulomatosis, relapse

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Documented diagnosis of Wegener's Granulomatosis (WG) according to the American College of Rheumatology classification criteria.
  2. Diagnosis of WG at least 6 months before entry and initial induction therapy with a combination of Glucocorticoids and an immunosuppressive (Cyclophosphamide or Methotrexate) or rituximab.
  3. Relapse of WG with or without ongoing Glucocorticoids, and/or immunosuppressive therapy with Azathioprine/Mycophenolate Mofetil/Methotrexate or Leflunomide. The minimum disease activity is defined by the presence of one new/worse major or three new/worse minor BVAS (version 3) items.
  4. Patients between 18 - 75 years.
  5. Medically acceptable and reliable contraception method during the study course. (Women should not become pregnant for at least 6 months after Cyclophosphamide treatment).
  6. Written informed consent for study participation given by the patient.
  7. Patients able and prepared to self-administer the study medication or having a relative/third person able to do it.
  8. Ability to read, understand and record information required by protocol

Exclusion Criteria:

  1. Other multi-system autoimmune disorders, including systemic lupus erythematosus and anti-Glomerular Basement Membrane disease.
  2. Systemic vasculitis due to a viral infection.
  3. Cyclophosphamide therapy intolerance, hypersensitivity or contraindication to Cyclophosphamide (active substance or any of the excipients) in patients with severe relapse of WG.
  4. Hypersensitivity or contraindication to

    • Spanidin (active substance or any of the excipients) or
    • both Methotrexate (active substance or any of the excipients) and Azathioprine(active substance or any of the excipients) or
    • methylprednisolone, prednisolone or other corticosteroids (active substance or any of the excipients).
  5. Underlying medical conditions, which in the opinion of the Investigator place the patient at an unacceptable risk level for participating in a study.
  6. Previous randomisation in this study.
  7. Cyclophosphamide , intravenous immunoglobulin, anti-cytokine biologic therapies, plasma exchange or Abatacept in the three months prior to entry to the trial. Rituximab, Alemtuzumab or stem cell transplantation is not permitted in the six months prior to entry to the trial.
  8. Previous treatment with gusperimus.
  9. Participation in another clinical trial with investigational drugs within the last 3 months before screening or during the present trial period.
  10. Pregnant or breast-feeding females.
  11. Active bacterial/viral infection (Human Immunodeficiency Virus, Hepatitis B, Hepatitis C, Tuberculosis).
  12. Patients with Glomerular Filtration Rate (eGFR) < 15 mL/min/1.73m2.
  13. Alanine transaminase (ALT), Aspartate aminotransferase (AST), bilirubin, and Alkaline phosphatase (ALP) levels above 2 x the upper normal limit.
  14. Inadequate bone-marrow function: White Blood Cells (WBC) < 4000/mm3, haemoglobin < 8 g/dL, neutrophils < 2500/mm3, platelets < 100 000/mm3.

Sites / Locations

  • Všeobecná fakultní nemocnice v Praze

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Test group - gusperimus

Control group

Arm Description

Both severity subgroups (severe and non-severe) will be treated with gusperimus + glucocorticoids.

The severe subgroup will receive a course (13 - 22 weeks) of cyclophosphamide followed by methotrexate + glucocorticoids. Patients intolerant to methotrexate and patients with impaired renal function will receive azathioprine + glucocorticoids. The non-severe subgroup will receive methotrexate + glucocorticoids(or azathioprine + glucocorticoids for those previously intolerant to methotrexate or with impaired renal function).

Outcomes

Primary Outcome Measures

Response rate
The primary efficacy variable is the rate of patients showing a response, with the level of disease activity Birmingham Vasculitis Activity Score (BVAS) ≤ 2, within 24 weeks of trial entry, which is maintained without relapse until the end of the trial (Week 52). The primary efficacy endpoint includes: i) Remission - defined as the complete absence of active clinical disease, i.e. a BVAS score of 0, for at least two months on a stable prednisone dose of ≤ 10 mg/day. ii) Low activity Disease State - persistence of up to two minor BVAS items (BVAS ≤ 2).

Secondary Outcome Measures

Time to response
Time to response (response is defined as the time from study entry to the first occasion that BVAS is ≤ 2, and there has been adherence to the steroid reduction protocol)
Response duration
Response duration defined as time from response with BVAS≤2 to relapse (relapse is defined as the return or first occurrence of one major and/or three minor BVAS items)
Frequency of severe relapses
Frequency of severe relapses (defined as at least one major BVAS item)
Vasculitis Damage Index (VDI) score change
VDI score change from baseline to month 12
Glomerular Filtration Rate (eGFR) change
eGFR change from baseline to month 12 in all patients and in a subgroup defined as having a baseline eGFR ≤ 60mL/min (i.e. renal impairment at baseline)
Frequency of Adverse Events (AEs) and Serious Adverse Event (SAEs)
Frequency of AEs and SAEs. (Total number of AEs per group according to AE category) (Percentage of patients in each group with a severe AE)
Frequency of severe infection
Frequency of severe infection (a severe infection is defined as an infection that requires intravenous antibiotics or hospitalisation).(Percentage of patients in each group with a severe infection)
Pharmacokinetic parameters at selected sites
Pharmacokinetic parameters Area Under the plasmaconcentration - time Curve (AUC), Maximum concentration reached in plasma (Cmax), Time to maximum concentration reached in plasma (Tmax) and Elimination half life in plasma (T½) calculated from the measured plasma samples collected at regular time intervals after administration of gusperimus on the first day of three treatment cycles
Short-Form-36 (SF-36)
Pooled physical and mental SF-36 domains change from baseline to month 6
Short-Form-36 (SF-36)
Pooled physical and mental SF-36 domains change from baseline to month 12
Total corticosteroid exposure
The total corticosteroid exposure
Questionnaire EQ-5D
Change in EQ-5D between baseline and month 12
Frequency of non-severe relapses
Frequency of non-severe relapses (defined as at least 3 minor BVAS items with no major BVAS items).

Full Information

First Posted
September 20, 2011
Last Updated
May 28, 2015
Sponsor
Nordic Pharma SAS
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1. Study Identification

Unique Protocol Identification Number
NCT01446211
Brief Title
Clinical Study Comparing the New Immunosuppressive Drug Gusperimus With the Conventional Treatment in Wegener's Granulomatosis
Acronym
SPARROW
Official Title
Randomised, Evaluator-Blinded, Multicentre, International, Parallel-Group, Active-Controlled Clinical Trial of Gusperimus Versus Conventional Therapy in Relapse of Granulomatosis With Polyangiitis (Wegener's Granulomatosis) SPARROW Study - SPAnidin in Relapsing GRanulomatosis With POlyangiitis Wegener's Granulomatosis)
Study Type
Interventional

2. Study Status

Record Verification Date
January 2015
Overall Recruitment Status
Terminated
Why Stopped
Change of design consideration
Study Start Date
November 2011 (undefined)
Primary Completion Date
November 2012 (Actual)
Study Completion Date
January 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Nordic Pharma SAS

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The aim of the study is to assess the efficacy (superiority testing) of gusperimus compared to conventional treatment in patients with a relapse of Wegener Granulomatosis with or without ongoing steroids, and/or immunosuppressive therapy. Further, to evaluate the safety and quality of life of gusperimus treatment compared to standard treatment in patients with relapse of Wegener Granulomatosis receiving glucocorticoids.
Detailed Description
Wegener Granulomatosis without treatment is life-threatening. The standard treatment with corticosteroids and cyclophosphamide is usually effective at controlling active disease. However, disease relapse is frequent and requires increased exposure to these toxic drugs. In other patients initiation or continuation of these standard drugs is contraindicated due to intolerable side effects. No well-established therapy is available for relapsing patients. They may suffer severe organ damage due to progressive disease, or may die. The proposed indication for gusperimus is the treatment of relapsing Wegener Granulomatosis. The aim of therapy with gusperimus is to induce and maintain remission thereby avoiding further cyclophosphamide and reducing corticosteroid exposure.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Wegeners Granulomatosis
Keywords
gusperimus, Wegeners granulomatosis, relapse

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
4 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Test group - gusperimus
Arm Type
Experimental
Arm Description
Both severity subgroups (severe and non-severe) will be treated with gusperimus + glucocorticoids.
Arm Title
Control group
Arm Type
Active Comparator
Arm Description
The severe subgroup will receive a course (13 - 22 weeks) of cyclophosphamide followed by methotrexate + glucocorticoids. Patients intolerant to methotrexate and patients with impaired renal function will receive azathioprine + glucocorticoids. The non-severe subgroup will receive methotrexate + glucocorticoids(or azathioprine + glucocorticoids for those previously intolerant to methotrexate or with impaired renal function).
Intervention Type
Drug
Intervention Name(s)
Gusperimus + glucocorticoids
Intervention Description
Both severity subgroups will be treated with gusperimus + glucocorticoids up to 12 months.
Intervention Type
Drug
Intervention Name(s)
cyclophosphamide followed by methotrexate (azathioprine) + glucocorticoids or methotrexate (azathioprine) + glucocorticoids
Intervention Description
Severe subgroup: will receive intravenous cyclophosphamide pulses for at least 13 weeks and 22 weeks at maximum, followed by methotrexate + glucocorticoids after achieving a response with BVAS ≤ 2. Patients intolerant to methotrexate and patients with impaired renal function will receive azathioprine + glucocorticoids . Non-severe subgroup: will receive methotrexate + glucocorticoids (or azathioprine + glucocorticoids for those previously intolerant to methotrexate or with impaired renal function).
Primary Outcome Measure Information:
Title
Response rate
Description
The primary efficacy variable is the rate of patients showing a response, with the level of disease activity Birmingham Vasculitis Activity Score (BVAS) ≤ 2, within 24 weeks of trial entry, which is maintained without relapse until the end of the trial (Week 52). The primary efficacy endpoint includes: i) Remission - defined as the complete absence of active clinical disease, i.e. a BVAS score of 0, for at least two months on a stable prednisone dose of ≤ 10 mg/day. ii) Low activity Disease State - persistence of up to two minor BVAS items (BVAS ≤ 2).
Time Frame
52 weeks
Secondary Outcome Measure Information:
Title
Time to response
Description
Time to response (response is defined as the time from study entry to the first occasion that BVAS is ≤ 2, and there has been adherence to the steroid reduction protocol)
Time Frame
From the date of study entry until the first occasion that BVAS is ≤ 2, assessed up to 52 weeks
Title
Response duration
Description
Response duration defined as time from response with BVAS≤2 to relapse (relapse is defined as the return or first occurrence of one major and/or three minor BVAS items)
Time Frame
From the date of response with BVAS≤2 until relapse, assessed up to 48 weeks
Title
Frequency of severe relapses
Description
Frequency of severe relapses (defined as at least one major BVAS item)
Time Frame
Up to 52 weeks
Title
Vasculitis Damage Index (VDI) score change
Description
VDI score change from baseline to month 12
Time Frame
12 months
Title
Glomerular Filtration Rate (eGFR) change
Description
eGFR change from baseline to month 12 in all patients and in a subgroup defined as having a baseline eGFR ≤ 60mL/min (i.e. renal impairment at baseline)
Time Frame
12 months
Title
Frequency of Adverse Events (AEs) and Serious Adverse Event (SAEs)
Description
Frequency of AEs and SAEs. (Total number of AEs per group according to AE category) (Percentage of patients in each group with a severe AE)
Time Frame
Up to 52 weeks
Title
Frequency of severe infection
Description
Frequency of severe infection (a severe infection is defined as an infection that requires intravenous antibiotics or hospitalisation).(Percentage of patients in each group with a severe infection)
Time Frame
Up to 52 weeks
Title
Pharmacokinetic parameters at selected sites
Description
Pharmacokinetic parameters Area Under the plasmaconcentration - time Curve (AUC), Maximum concentration reached in plasma (Cmax), Time to maximum concentration reached in plasma (Tmax) and Elimination half life in plasma (T½) calculated from the measured plasma samples collected at regular time intervals after administration of gusperimus on the first day of three treatment cycles
Time Frame
1st day of gusperimus cycles 1, 6 or 7, 12 or 13
Title
Short-Form-36 (SF-36)
Description
Pooled physical and mental SF-36 domains change from baseline to month 6
Time Frame
6 months
Title
Short-Form-36 (SF-36)
Description
Pooled physical and mental SF-36 domains change from baseline to month 12
Time Frame
12 months
Title
Total corticosteroid exposure
Description
The total corticosteroid exposure
Time Frame
Up to 52 weeks
Title
Questionnaire EQ-5D
Description
Change in EQ-5D between baseline and month 12
Time Frame
12 months
Title
Frequency of non-severe relapses
Description
Frequency of non-severe relapses (defined as at least 3 minor BVAS items with no major BVAS items).
Time Frame
Up to 52 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Documented diagnosis of Wegener's Granulomatosis (WG) according to the American College of Rheumatology classification criteria. Diagnosis of WG at least 6 months before entry and initial induction therapy with a combination of Glucocorticoids and an immunosuppressive (Cyclophosphamide or Methotrexate) or rituximab. Relapse of WG with or without ongoing Glucocorticoids, and/or immunosuppressive therapy with Azathioprine/Mycophenolate Mofetil/Methotrexate or Leflunomide. The minimum disease activity is defined by the presence of one new/worse major or three new/worse minor BVAS (version 3) items. Patients between 18 - 75 years. Medically acceptable and reliable contraception method during the study course. (Women should not become pregnant for at least 6 months after Cyclophosphamide treatment). Written informed consent for study participation given by the patient. Patients able and prepared to self-administer the study medication or having a relative/third person able to do it. Ability to read, understand and record information required by protocol Exclusion Criteria: Other multi-system autoimmune disorders, including systemic lupus erythematosus and anti-Glomerular Basement Membrane disease. Systemic vasculitis due to a viral infection. Cyclophosphamide therapy intolerance, hypersensitivity or contraindication to Cyclophosphamide (active substance or any of the excipients) in patients with severe relapse of WG. Hypersensitivity or contraindication to Spanidin (active substance or any of the excipients) or both Methotrexate (active substance or any of the excipients) and Azathioprine(active substance or any of the excipients) or methylprednisolone, prednisolone or other corticosteroids (active substance or any of the excipients). Underlying medical conditions, which in the opinion of the Investigator place the patient at an unacceptable risk level for participating in a study. Previous randomisation in this study. Cyclophosphamide , intravenous immunoglobulin, anti-cytokine biologic therapies, plasma exchange or Abatacept in the three months prior to entry to the trial. Rituximab, Alemtuzumab or stem cell transplantation is not permitted in the six months prior to entry to the trial. Previous treatment with gusperimus. Participation in another clinical trial with investigational drugs within the last 3 months before screening or during the present trial period. Pregnant or breast-feeding females. Active bacterial/viral infection (Human Immunodeficiency Virus, Hepatitis B, Hepatitis C, Tuberculosis). Patients with Glomerular Filtration Rate (eGFR) < 15 mL/min/1.73m2. Alanine transaminase (ALT), Aspartate aminotransferase (AST), bilirubin, and Alkaline phosphatase (ALP) levels above 2 x the upper normal limit. Inadequate bone-marrow function: White Blood Cells (WBC) < 4000/mm3, haemoglobin < 8 g/dL, neutrophils < 2500/mm3, platelets < 100 000/mm3.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
David Jayne, MD
Organizational Affiliation
Addenbrookes Hospital, Cambridge, United Kingdom
Official's Role
Principal Investigator
Facility Information:
Facility Name
Všeobecná fakultní nemocnice v Praze
City
Praha
ZIP/Postal Code
128 08
Country
Czech Republic

12. IPD Sharing Statement

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Clinical Study Comparing the New Immunosuppressive Drug Gusperimus With the Conventional Treatment in Wegener's Granulomatosis

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