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

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)

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.

Study Overview

• Status: Terminated
• Conditions: Wegeners Granulomatosis
• Intervention / Treatment: Drug: Gusperimus + glucocorticoids; Drug: cyclophosphamide followed by methotrexate (azathioprine) + glucocorticoids or methotrexate (azathioprine) + 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.

• Study Type: Interventional
• Enrollment (Actual): 4
• Phase: Phase 3

Contacts and Locations

Study Locations

• Czech Republic
  • Praha, Czech Republic, 128 08
    • Vseobecna Fakultni Nemocnice V Praze

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 73 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Test group - gusperimus; Both severity subgroups (severe and non-severe) will be treated with gusperimus + glucocorticoids.	Drug: Gusperimus + glucocorticoids; Both severity subgroups will be treated with gusperimus + glucocorticoids up to 12 months.
Active Comparator: Control group; 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).	Drug: cyclophosphamide followed by methotrexate (azathioprine) + glucocorticoids or methotrexate (azathioprine) + glucocorticoids; 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).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	52 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	From the date of study entry until the first occasion that BVAS is ≤ 2, assessed up to 52 weeks
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)	From the date of response with BVAS≤2 until relapse, assessed up to 48 weeks
Frequency of severe relapses	Frequency of severe relapses (defined as at least one major BVAS item)	Up to 52 weeks
Vasculitis Damage Index (VDI) score change	VDI score change from baseline to month 12	12 months
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)	12 months
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)	Up to 52 weeks
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)	Up to 52 weeks
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	1st day of gusperimus cycles 1, 6 or 7, 12 or 13
Short-Form-36 (SF-36)	Pooled physical and mental SF-36 domains change from baseline to month 6	6 months
Short-Form-36 (SF-36)	Pooled physical and mental SF-36 domains change from baseline to month 12	12 months
Total corticosteroid exposure	The total corticosteroid exposure	Up to 52 weeks
Questionnaire EQ-5D	Change in EQ-5D between baseline and month 12	12 months
Frequency of non-severe relapses	Frequency of non-severe relapses (defined as at least 3 minor BVAS items with no major BVAS items).	Up to 52 weeks

Collaborators and Investigators

• Sponsor: Nordic Pharma SAS
• Investigators: Principal Investigator: David Jayne, MD, Addenbrookes Hospital, Cambridge, United Kingdom

Study record dates

Study Major Dates

• Study Start: November 1, 2011
• Primary Completion (Actual): November 1, 2012
• Study Completion (Actual): January 1, 2015

Study Registration Dates

• First Submitted: September 20, 2011
• First Submitted That Met QC Criteria: October 4, 2011
• First Posted (Estimate): October 5, 2011

Study Record Updates

• Last Update Posted (Estimate): May 29, 2015
• Last Update Submitted That Met QC Criteria: May 28, 2015
• Last Verified: January 1, 2015

More Information

Terms related to this study

• Keywords: relapse; gusperimus; Wegeners granulomatosis
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Immune System Diseases; Autoimmune Diseases; Lung Diseases; Vasculitis; Lung Diseases, Interstitial; Systemic Vasculitis; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Granulomatosis with Polyangiitis; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protective Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Dermatologic Agents; Antibiotics, Antineoplastic; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Radiation-Protective Agents; Cyclophosphamide; Methotrexate; Azathioprine; Glucocorticoids; Gusperimus
• Other Study ID Numbers: NO005-NK103; 2011-001219-30 (EudraCT Number)