ANCA Associated VasculitisPhase 3ENDURRANCE-1NCT03942887
Exploring Durable Remission With Rituximab in Antineutrophil Cytoplasmic Antibody(ANCA)-Associated Vasculitis
A Phase 3 study testing Rituximab, endoxan and Methylprednisolone in people with ANCA Associated Vasculitis, run by Leiden University Medical Center at 4 sites in Netherlands.
Trial summary
Most recent insights in the treatment for patients with ANCA-associated vasculitis (AAV) have demonstrated that 'tailored' maintenance treatment with rituximab (RTX) is effective to achieve durable remission of disease. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- ANCA Associated Vasculitis
- What is being tested?
- Rituximab, endoxan and Methylprednisolone
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 100 participants
- Where
- 4 sitesNetherlands
- Study dates
- 3 May 2019to 1 Apr 2025
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Subjects enrolled in the study must meet the following inclusion criteria:
- Clinical diagnosis of granulomatosis with polyangiitis (GPA) or microscopic Polyangiitis (MPA), consistent with Chapel-Hill Consensus Conference definitions26
- Aged at least 18 years, with newly-diagnosed or relapsed AAV with 'generalised disease', defined as involvement of at least one major organ (e.g. kidney, lung, heart, peripheral or central nervous system), requiring induction treatment with cyclophosphamide or rituximab
- Positive test for anti-PR3 or anti-MPO (current or historic)
- Willing and able to give written Informed Consent and to comply with the requirements of the study protocol
Who cannot join
- Subjects will be excluded from participation if they meet any of the following exclusion criteria:
- Pregnant or breast-feeding
- Active pregnancy, as proven by a positive urine beta-HCG test or a positive serum beta-HCG
- Significant hypogammaglobulinemia (IgG < 4.0 g/L) or an IgA deficiency (IgA < 0.1 g/L)
- Active infection not compatible with start of remission-induction therapy in the opinion of the treating physician and/or investigator, e.g.:
- Serological evidence of viral hepatitis defined as: patients positive for HbsAg test or HBcAb or a positive hepatitis C antibody not treated with antiviral medication
Show all 17Show fewer
- Have a historically positive HIV test or test positive at screening for HIV
- Have a history of a primary immunodeficiency
- Have a significant infection history that in the opinion of the investigator would make the candidate unsuitable for the study
- Have a neutrophil count of < 1.5x10E9/L
- Evidence of hepatic disease: AST, ALT, alkaline phosphatase, or bilirubin > 3 times the upper limit of normal before start of dosing
- Have any other clinically significant abnormal laboratory value in the opinion of the investigator
- Required dialysis or plasma exchange within 12 weeks prior to screening
- Received intravenous glucocorticoids, >3000mg methylprednisolone equivalent, within 4 weeks prior to screening
- Immunization with a live vaccine 1 month before screening
- History or presence of any medical condition or disease which, in the opinion of the Investigator, may place the patient at unacceptable risk for study participation.
- Have a history of an anaphylactic reaction to parenteral administration of contrast agents, human or murine proteins or monoclonal antibodies
Trial locations and contacts
4 sites in 1 country.
Netherlands4 sites, 4 recruiting
- Not yet recruiting
Noordwest Ziekenhuisgroep
Alkmaar
- Recruiting
Meander Medical Center
Amersfoort
- Recruiting
Leiden University Medical Center
Leiden, South Holland, 2333ZA
YKO Teng, MD, PhD, +31715268157, y.k.o.teng@lumc.nl
- Not yet recruiting
HagaZiekenhuis
The Hague
About this study
Official title: Evaluating Clinical and Immunological Effects of Rituximab With Cyclophosphamide Compared to Rituximab Alone in AAV Patients
Most recent insights in the treatment for patients with ANCA-associated vasculitis (AAV) have demonstrated that 'tailored' maintenance treatment with rituximab (RTX) is effective to achieve durable remission of disease. As such, RTX re-treatment can be tailored on the basis of relevant clinical and immunological parameters in AAV patients. Now, the present study intends to evaluate whether combining rituximab with cyclophosphamide is superior to current standard of care with rituximab only to induce a favorable clinical and immunological state in AAV patients and can thereby reduce the number of tailored re-treatments with rituximab.
Read the detailed description
Objectives: The primary objective is to prove that the combination of RTX and low-dose CYC reduces the number of RTX infusions needed to maintain clinical remission over 2 years. The secondary objectives are measurements for minimal residual auto-immunity (MRA) such as time to ANCA seronegativity, proportion of seronegativity, time to ANCA return, proportion of ANCA return, duration of B-cell depletion and the composition of the memory B-cell and plasma cell populations. Other secondary objectives are the potential association between MRA and disease flares, and the evaluation of (severe) adverse events, cost-effectiveness and quality of life Study design: open-label, multicenter, 1:1 randomized, prospective study Study population: Adult AAV patients with a clinical diagnosis of granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) who have 'generalised disease' and a positive ANCA-test for anti-PR3 or anti-MPO.
Intervention: In addition to standard of care corticosteroid therapy, AAV patients will be randomized to receive either standard induction therapy with 2 infusions of RTX 1000 mg or induction therapy combining 2 infusions of RTX 1000 mg with 6 infusions of low dose intravenous cyclophosphamide 500mg. Thereafter, as part of standard of care patients will receive tailored RTX re-treatment as maintenance therapy.
Main study parameters: AAV patients will be evaluated for the cumulative number of events for tailored RTX retreatments needed to maintain clinical remission over 2 years. Also, AAV patients will be evaluated for MRA by prospectively and consecutively studying ANCA levels and B-cell depletion by standard flowcytometry at predefined timepoints. Additionally, the study will perform safety and toxicity monitoring according to WHO toxicity criteria and evaluate the clinical response, the number of moderate and severe flares during study follow-up, the cost-effectiveness, and the quality of life of patients.
Study duration: 2 years
- Conditions
- ANCA Associated Vasculitis
- Being tested
- Rituximab, endoxan, Methylprednisolone, Prednisolone
- Keywords
- ANCA, Crescentic glomerulonephritis, systemic autoimmune disease, Renal failure, Renal insufficiency, small vessel vasculitis, GPA, MPA
- Medical subject headings
- Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis, Renal Insufficiency
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
RituximabDrug
Also called anti-cd20
Patients will be intravenously treated with Rituximab 1000mg (or biosimilar) in the first week and receive a 2nd dosage of 1000mg 14 days later. Before every infusion of Rituximab patients will receive intravenous methylprednisolone 100mg together with oral acetaminophen 1000 mg and and intravenous Tavegil 2 mg. At any time during the study, a rituximab biosimilar is allowed as a substitute for the bio-originator rituximab.
endoxanDrug
Also called cyclophosphamide
Patients will be intravenously treated with a total of 6 infusions of cyclophosphamide 500mg every 2 weeks. Before every infusion of cyclophosphamide patients will receive intravenous granisetron to prevent nausea.
Also called solumedrol
Patients are given 1-3 pulses of 500mg methylprednisolone i.v. up to a maximum cumulative dose of 3000mg, taking into account any doses of intravenous methylprednisolone administered within 12 weeks prior to screening.
PrednisoloneDrug
Also called corticosteroid
after intravenous pulse methylprednisolone, oral prednisolone will be given at a dose of 1mg/kg daily and tapered according to the recommendations
| Study group | Role | What they receive |
|---|---|---|
| Rituximab | Active comparator | Patients will be intravenously treated with Rituximab 1000mg (or biosimilar) in the first week and receive a 2nd dosage of 1000mg 14 days later. Before every infusion of Rituximab patients will receive intravenous methylprednisolone 100mg together with oral acetaminophen 1000 mg and and intravenous Tavegil 2 mg. Receives: Drug: Rituximab; Drug: Methylprednisolone; Drug: Prednisolone |
| Rituximab plus low-dose cyclophosphamide | Active comparator | 5.1.2. Cyclophosphamide Patients will be intravenously treated with a total of 6 infusions of cyclophosphamide 500mg every 2 weeks. Before every infusion of cyclophosphamide patients will receive intravenous granisetron to prevent nausea. Receives: Drug: Rituximab; Drug: endoxan; Drug: Methylprednisolone; Drug: Prednisolone |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of tailored RTX infusions
The primary outcome is the number of RTX infusions needed to maintain clinical remission over 2 years
Measured: 2 years
Secondary outcomes (10)
Time
- time to a ANCA negative test
Measured: 2 years
ANCA reappearance
- Percentage of patients that have ANCA return during follow-up
Measured: 2 years
B cell depletion
- duration of B-cell depletion
Measured: 2 years
Remission and relaps rate
- to compare disease controle between arms
Measured: 2 years
Number of adverse events
- to assess the safety parameters of each treatment arm including adverse events according to WHO toxicity criteria, time to immune reconstitution and recording of infectious events
Measured: 2 years
Quality of Life by AAV-PRO
assess quality of life by AAV-PRO
Measured: 2 years
BVAS
Disease activity will be assessed by BVAS
Measured: 2 years
concomitant immunosuppressants
Disease activity assessed by (the reduction of) concomitant immunosuppressants
Measured: 2 years
Kidney function
Return of kidney function will be assessed.
Measured: 2 years
Biomarker for inflammation
Disease activity assessed by ESR
Measured: 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 May 2019
- Study start3 May 2019
- Primary completion1 Apr 2025 (estimated)
- Study completion1 Apr 2025 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for ANCA Associated VasculitisStudies of the same condition, open and under way.
- More trials run by Leiden University Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- open-label, 1:1 randomized, prospective study between RTX with cyclophosphamide and RTX alone.
- Masking
- None (open label)
- Enrolment
- 100 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Leiden University Medical Center
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Y.K.Onno Teng, Leiden University Medical Center
- Investigators
- YKO Teng, MD, PhD, Principal investigator, LUMC Leiden
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03942887
- Sponsor's protocol ID
- NL67515.058.18
- Acronym
- ENDURRANCE-1
- Status last verified
- Dec 2023
- First submitted
- 8 Apr 2019
- Last updated
- 14 Dec 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Dirikgil E, van Leeuwen JR, Bredewold OW, Ray A, Jonker JT, Soonawala D, Remmelts HHF, van Dam B, Bos WJ, van Kooten C, Rotmans J, Rabelink T, Teng YKO. ExploriNg DUrable Remission with Rituximab in ANCA-associatEd vasculitis (ENDURRANCE trial): protocol for a randomised controlled trial. BMJ Open. 2022 Sep 21;12(9):e061339. doi: 10.1136/bmjopen-2022-061339.
PubMed 36130755
Study at a glance
From the registry record, last updated by the sponsor on 14 Dec 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Evaluating Clinical and Immunological Effects of Rituximab With Cyclophosphamide Compared to Rituximab Alone in AAV Patients
- ClinicalTrials.gov ID
- NCT03942887
- Acronym / sponsor ID
- ENDURRANCE-1 / NL67515.058.18
- Conditions
- ANCA Associated Vasculitis
- Keywords
- ANCA, Crescentic glomerulonephritis, systemic autoimmune disease, Renal failure, Renal insufficiency, small vessel vasculitis, GPA, MPA
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 100 participants (estimated)
- Lead sponsor
- Leiden University Medical CenterUniversity, hospital or other
- Study start
- 3 May 2019 (actual)
- Primary completion
- 1 Apr 2025 (estimated)
- Study completion
- 1 Apr 2025 (estimated)
- First posted
- 8 May 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Most recent insights in the treatment for patients with ANCA-associated vasculitis (AAV) have demonstrated that 'tailored' maintenance treatment with rituximab (RTX) is effective to achieve durable remission of disease. As such, RTX re-treatment can be tailored on the basis of relevant clinical and immunological parameters in AAV patients. Now, the present study intends to evaluate whether combining rituximab with cyclophosphamide is superior to current standard of care with rituximab only to induce a favorable clinical and immunological state in AAV patients and can thereby reduce the number of tailored re-treatments with rituximab.
Detailed description
Objectives: The primary objective is to prove that the combination of RTX and low-dose CYC reduces the number of RTX infusions needed to maintain clinical remission over 2 years. The secondary objectives are measurements for minimal residual auto-immunity (MRA) such as time to ANCA seronegativity, proportion of seronegativity, time to ANCA return, proportion of ANCA return, duration of B-cell depletion and the composition of the memory B-cell and plasma cell populations. Other secondary objectives are the potential association between MRA and disease flares, and the evaluation of (severe) adverse events, cost-effectiveness and quality of life Study design: open-label, multicenter, 1:1 randomized, prospective study Study population: Adult AAV patients with a clinical diagnosis of granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) who have 'generalised disease' and a positive ANCA-test for anti-PR3 or anti-MPO.
Intervention: In addition to standard of care corticosteroid therapy, AAV patients will be randomized to receive either standard induction therapy with 2 infusions of RTX 1000 mg or induction therapy combining 2 infusions of RTX 1000 mg with 6 infusions of low dose intravenous cyclophosphamide 500mg. Thereafter, as part of standard of care patients will receive tailored RTX re-treatment as maintenance therapy.
Main study parameters: AAV patients will be evaluated for the cumulative number of events for tailored RTX retreatments needed to maintain clinical remission over 2 years. Also, AAV patients will be evaluated for MRA by prospectively and consecutively studying ANCA levels and B-cell depletion by standard flowcytometry at predefined timepoints. Additionally, the study will perform safety and toxicity monitoring according to WHO toxicity criteria and evaluate the clinical response, the number of moderate and severe flares during study follow-up, the cost-effectiveness, and the quality of life of patients.
Study duration: 2 years
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- open-label, 1:1 randomized, prospective study between RTX with cyclophosphamide and RTX alone.
| Arm | Type | Receives |
|---|---|---|
| Rituximab | Active comparator | Drug: Rituximab, Drug: Methylprednisolone, Drug: PrednisolonePatients will be intravenously treated with Rituximab 1000mg (or biosimilar) in the first week and receive a 2nd dosage of 1000mg 14 days later. Before every infusion of Rituximab patients will receive intravenous methylprednisolone 100mg together with oral acetaminophen 1000 mg and and intravenous Tavegil 2 mg. |
| Rituximab plus low-dose cyclophosphamide | Active comparator | Drug: Rituximab, Drug: endoxan, Drug: Methylprednisolone, Drug: Prednisolone5.1.2. Cyclophosphamide Patients will be intravenously treated with a total of 6 infusions of cyclophosphamide 500mg every 2 weeks. Before every infusion of cyclophosphamide patients will receive intravenous granisetron to prevent nausea. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- Clinical diagnosis of granulomatosis with polyangiitis (GPA) or microscopic Polyangiitis (MPA), consistent with Chapel-Hill Consensus Conference definitions26
- Aged at least 18 years, with newly-diagnosed or relapsed AAV with 'generalised disease', defined as involvement of at least one major organ (e.g. kidney, lung, heart, peripheral or central nervous system), requiring induction treatment with cyclophosphamide or rituximab
- Positive test for anti-PR3 or anti-MPO (current or historic)
- Willing and able to give written Informed Consent and to comply with the requirements of the study protocol
Key exclusion criteria (17 listed)
- Subjects will be excluded from participation if they meet any of the following exclusion criteria:
- Pregnant or breast-feeding
- Active pregnancy, as proven by a positive urine beta-HCG test or a positive serum beta-HCG
- Significant hypogammaglobulinemia (IgG < 4.0 g/L) or an IgA deficiency (IgA < 0.1 g/L)
- Active infection not compatible with start of remission-induction therapy in the opinion of the treating physician and/or investigator, e.g.:
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| RituximabAlso: anti-cd20Patients will be intravenously treated with Rituximab 1000mg (or biosimilar) in the first week and receive a 2nd dosage of 1000mg 14 days later. Before every infusion of Rituximab patients will receive intravenous methylprednisolone 100mg together with oral acetaminophen 1000 mg and and intravenous Tavegil 2 mg. At any time during the study, a rituximab biosimilar is allowed as a substitute for the bio-originator rituximab. | Drug | Rituximab, Rituximab plus low-dose cyclophosphamide |
| endoxanAlso: cyclophosphamidePatients will be intravenously treated with a total of 6 infusions of cyclophosphamide 500mg every 2 weeks. Before every infusion of cyclophosphamide patients will receive intravenous granisetron to prevent nausea. | Drug | Rituximab plus low-dose cyclophosphamide |
| MethylprednisoloneAlso: solumedrolPatients are given 1-3 pulses of 500mg methylprednisolone i.v. up to a maximum cumulative dose of 3000mg, taking into account any doses of intravenous methylprednisolone administered within 12 weeks prior to screening. | Drug | Rituximab, Rituximab plus low-dose cyclophosphamide |
| PrednisoloneAlso: corticosteroidafter intravenous pulse methylprednisolone, oral prednisolone will be given at a dose of 1mg/kg daily and tapered according to the recommendations | Drug | Rituximab, Rituximab plus low-dose cyclophosphamide |
Primary outcome
Number of tailored RTX infusions
Time frame: 2 years
The primary outcome is the number of RTX infusions needed to maintain clinical remission over 2 years
10 secondary outcomes
Time
Time frame: 2 years
ANCA reappearance
Time frame: 2 years
B cell depletion
Time frame: 2 years
Remission and relaps rate
Time frame: 2 years
Number of adverse events
Time frame: 2 years
Quality of Life by AAV-PRO
Time frame: 2 years
BVAS
Time frame: 2 years
concomitant immunosuppressants
Time frame: 2 years
Kidney function
Time frame: 2 years
Biomarker for inflammation
Time frame: 2 years
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 Dec 2023.
- Derived from this study: PubMed 36130755Dirikgil E, van Leeuwen JR, Bredewold OW, Ray A, Jonker JT, Soonawala D, Remmelts HHF, van Dam B, Bos WJ, van Kooten C, Rotmans J, Rabelink T, Teng YKO. ExploriNg DUrable Remission with Rituximab in ANCA-associatEd vasculitis (ENDURRANCE trial): protocol for a randomised controlled trial. BMJ Open. 2022 Sep 21;12(9):e061339. doi: 10.1136/bmjopen-2022-061339.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
YKO Teng, MD, PhD principal investigator
LUMC Leiden
4 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Rituximab, endoxan and Methylprednisolone in people with ANCA Associated Vasculitis, run by Leiden University Medical Center at 4 sites in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 14 Dec 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 4 sites in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact YKO Teng, MD, PhD (+31715262148, y.k.o.teng@Lumc.nl), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of tailored RTX infusions (time frame: 2 years). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03942887, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Dec 2023.