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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

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:

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.

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

NCT ID

NCT01446211

First Posted

September 20, 2011

Last Updated

May 28, 2015

Sponsor

Nordic Pharma SAS

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

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

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

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

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

Learn more about this trial

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

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