Comparison of the efficacy and safety of leflunomide versus placebo combined with basic prednisone therapy in patients with active disease phase of Takayasu arteritis: study protocol for a randomized, double-blinded controlled trial (Takayasu arteritis clinical trial in China: TACTIC)

Abstract

Background:

Takayasu arteritis (TAK) is an immune-induced granulomatous vasculitis that occurs primarily in young Asian women. Our previous cohort studies have indicated that leflunomide (LEF), which can lead to rapid induction and might be a promising alternative treatment for TAK.

Objectives:

To compare the efficacy and safety of LEF versus placebo combined with prednisone for active TAK in a Chinese population.

Design:

This will be a multicenter, randomized, double-blinded controlled trial aiming to recruit 116 TAK patients with active disease. This study will last 52 weeks.

Methods and analysis:

Participants will be assigned randomly to the LEF intervention arm or placebo control arm at a 1:1 ratio. Initially, LEF combined with prednisone will be given to the intervention arm and a placebo tablet combined with prednisone will be given to the placebo arm. At the end of week 24, subjects who achieved clinical remission or partial clinical remission will proceed to maintenance therapy with LEF to the end of week 52; those who did not achieve clinical remission or partial clinical remission in the LEF intervention arm will drop out from the study, and those in the placebo control arm will switch to LEF treatment to week 52. The primary endpoint will be the clinical remission rate of LEF versus placebo at the end of week 24. The secondary endpoints will be the time to clinical remission, mean dose of prednisone, disease recurrence, time to recurrence, adverse events, as well as clinical remission in subjects who switched from the placebo control arm to LEF therapy after week 24. Intention to treat will be the primary analysis.

Discussion:

This is the first randomized double-blinded placebo-controlled trial to clarify the efficacy and safety of LEF in treating active TAK. The results will provide more evidence for TAK management.

Registration:

ClinicalTrials.gov identifier: NCT02981979

Background

Takayasu arteritis (TAK) is an immune-induced granulomatous vasculitis which mainly involves the aorta and its main branches.^1,2 It usually occurs in young Asian women, and the pathogenesis of TAK is not known.^3,4 Persistent inflammation and subsequent vascular remodeling can lead to stenosis and occlusion of involved vessels, resulting eventually in the ischemia and dysfunction of organs.^5,6 Thus, timely and efficacious treatment is essential.

A combination of a glucocorticoid (GC) and one or more disease-modifying antirheumatic drug (DMARD) is first-line treatment for TAK.^7,8 In comparison with GC monotherapy, combination with DMARDs can prolong disease remission and help tapering of the GC dose.^9–11 However, evidence from high-quality studies, especially from randomized, double-blinded controlled trials, to ascertain the efficacy and safety of different DMARDs and which DMARDs should be the first-line choice is lacking. There are two systematic reviews published in 2021 reporting the efficacy of DMARDs including conventional DMARDs (cDMARDs) and biologic DMARDs (bDMARDs) in the TAK management.^12,13 All studies, in regard of cDMARDs [methotrexate, azathioprine, cyclophosphamide, mycophenolate mofetil, leflunomide (LEF), etc.], included in the systematic review were observational studies (14 uncontrolled and 7 controlled) with study sample ranging from 7 to 92 subjects.¹²

LEF is a traditional cDMARD. It can inhibit cell proliferation, suppress tyrosine kinase signaling, block the production of pro-inflammatory cytokines,^14–17 and has been successfully used in the treatment of rheumatoid arthritis.^18,19 However, data on the efficacy and safety of LEF in TAK treatment are scarce. A study of 15 TAK patients showed 80% cases treated with LEF could get disease remission.²⁰ A prolonged study with 4-year follow-up showed that 41.6% of patients who had LEF treatment continued to have sustained remission from disease.²¹ Our cohort studies have indicated that LEF can lead to rapid induction at 6 months (clinical remission: 80–85%) and disease remission could be sustained until 12 months with clinical remission of 70–80%.^22–24 Thus, LEF might be a promising alternative treatment for TAK.

We plan to conduct a multicenter, randomized, double-blinded controlled trial. Our aim is to compare the efficacy and safety of LEF versus placebo combined with prednisone for TAK in a Chinese population. The primary endpoint will be the clinical remission rate at the end of week 24. This trial is named the ‘Takayasu arteritis clinical trial in China’ (TACTIC; ClinicalTrials.gov identifier: NCT02981979).

Research design and methodology

Study design

TACTIC will last 52 weeks. It will be a randomized double-blinded placebo-controlled trial. Six clinical centers across China will participate in this trial. One-hundred and sixteen TAK patients with active disease will be recruited and assigned randomly to the LEF intervention arm or placebo control arm at a 1:1 ratio. Initially, LEF combined with prednisone will be given to patients in the intervention arm and a placebo tablet combined with prednisone will be given to individuals in the placebo arm. The primary endpoint will be the clinical remission rate of LEF versus placebo at the end of week 24. Participants who achieve clinical remission or partial clinical remission at the end of week 24 will progress to maintenance therapy with LEF from week 25 to the end of week 52. If participants do not satisfy the criteria for clinical remission or partial clinical remission at the end of week 24, unblinding will be undertaken. For the LEF intervention arm, the patient will drop out from the study. For the placebo control arm, the patient will receive LEF treatment to week 52 (Figure 1). A checklist complied with the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guidelines for trial protocols was shown as supplementary material.

Figure 1.

Study flow chart.

This is a randomized, double-blinded controlled trial aiming to recruit 116 TAK patients with active disease. Participants will be assigned randomly to the LEF intervention arm or placebo control arm at a 1:1 ratio. Initially, LEF combined with prednisone will be given to the intervention arm and a placebo tablet combined with prednisone will be given to the placebo arm. At the end of week 24, subjects who achieved clinical remission or partial clinical remission will proceed to maintenance therapy with LEF to the end of week 52; those who did not achieve clinical remission or partial clinical remission in the LEF intervention arm will quit the study, and those in the placebo control arm will switch to LEF treatment to week 52.

GCs, glucocorticoids; LEF, leflunomide. TAK, Takayasu arteritis.

Ethical approval (B2016-151) of the trial protocol has been received from the Ethics Committee of Zhongshan Hospital within Fudan University (Shanghai, China). Informed written consent will be obtained from all individuals before enrollment.

Inclusion criteria

1. Male or females aged 18–65 years diagnosed with TAK according to the classification criteria set by the American College of Rheumatology (ACR) in 1990.²⁵

2. With active disease within the last 3 months, meeting at least two of the following conditions:

   • a. New vascular ischemic manifestations/physical signs or systemic symptoms.
   • b. Erythrocyte sedimentation rate (ESR) evaluation or high-sensitivity C-reactive protein (hs-CRP) ⩾6 mg/l or C-reactive protein (CRP) ⩾10 mg/l without other confounding factors (e.g. infection).
   • c. Active vascular inflammation as indicated by contrast-enhanced computed tomography angiography (CTA), magnetic resonance angiography (MRA), color Doppler ultrasonography or positron emission tomography/CT (PET/CT).

• 3. Individuals did not receive LEF within 3 months before screening.

• 4. For individuals who received cyclophosphamide before screening, cyclophosphamide should be discontinued for ⩾8 weeks; for patients who received a biological agent before screening, biological agents (e.g. tocilizumab, rituximab, and inhibitors of tumor necrosis factor) should be discontinued for ⩾12 weeks.

• 5. For patients who were taking prednisone (or its equivalent) before screening, the dose should be ⩽0.6 mg/kg/day and the patient should be stable for ⩾4 weeks.

• 6. Pregnancy should not be planned and a pregnancy test should be negative.

Exclusion criteria

1. Individuals who had only vascular dilatation or aneurysm formation.

2. People who had received revascularization surgery within the previous 3 months.

3. Individuals with severe organ dysfunction meeting at least one of the following:

   • a. Heart dysfunction: New York Heart Association grade IV.

   • b. Renal dysfunction: estimated glomerular filtration rate ⩽60 ml/min.

   • c. Liver dysfunction: Child–Pugh grade ⩾2.

   • d. Neurologic severe ischemic event: amaurosis on 3 consecutive days, acute cerebral infarction, or cerebral hemorrhage.

   • e. Uncontrolled blood pressure >160/100 mmHg.

• 4. Individuals with at least one following abnormal laboratory test results:

  • a. Alanine aminotransferase or aspartate transaminase ⩾1.5-fold of the upper limit of normal in serum.

  • b. White blood cell count ⩽4 × 10⁹/l.

  • c. Platelet count ⩽100 × 10⁹/l.

  • d. Hemoglobin ⩽85 g/l.

• 5. Individuals with other types of autoimmune disease or uncontrolled asthma who need prednisone ⩾10 mg/day, with a history of malignant tumor or any serious acute/chronic infection, including positivity for hepatitis B surface antigen, hepatitis C antibody, or clinical/radiological/laboratory evidence of active tuberculosis.

• 6. Individuals allergic to any of the investigational drugs.

• 7. People with at least one of the following unacceptable treatments or medications:

  • a. Previous treatment with LEF for ⩾3 months but not efficacious.

  • b. Planning to receive an attenuated vaccine during the study period.

  • c. Planning to undergo (or have undergone) organ transplantation.

Avoidance of bias

Randomization and blinding

Participants will be assigned randomly to the LEF intervention arm or placebo control arm at a 1:1 ratio using stratified block randomization. Center randomization will be done by the Interactive Web Response System of the Biomedical Informatics and Statistics Center of Fudan University. Sequentially numbered, opaque, sealed envelopes will be used in order to maintain allocation concealment. Special and independent randomizer as well as drug administrator was set up throughout the whole study period to keep participants, investigators, as well as the clinical trial supervisor, coordinator, and statistical analyst, to be blinded to the intervention.

Unblinding

At the end of week 24, if clinical remission or partial clinical remission are achieved, patients will undergo maintenance therapy. If the participant does not achieve clinical remission or partial clinical remission at the end of week 24, unblinding will be undertaken.

An urgent unblinding procedure should be carried out if the participant (1) becomes pregnant, (2) suffers a severe adverse event that necessitates treatment, (3) suffers a drug overdose that necessitates further intervention.

Intervention

Prednisone

The recommended initial dose of prednisone for all enrolled patients will be 0.6 mg/kg/day. After 4 weeks, reduction of prednisone (5 mg/day every 2 weeks) or delayed reduction should be considered according to disease status as defined by investigators. Once the prednisone dose has been reduced to 10 mg/day, this dose should be maintained to the end of week 52.

LEF/placebo

For the LEF intervention arm, LEF (10 mg/tablet) will be administered at 20 mg/day. For the placebo control arm, LEF simulant (10 mg/tablet; the same color, taste, shape, and packaging of the LEF tablet) will be given at 20 mg/day. At the end of week 24, if clinical remission or partial clinical remission is achieved, the patient will proceed to maintenance therapy with LEF (20 mg/day) from week 25 to the end of week 52. If the patient does not meet the criteria for clinical remission or partial clinical remission at the end of week 24, unblinding should be carried out. Patients in the placebo control arm should switch to LEF (20 mg/day) to week 52, and patients in the LEF intervention arm should quit the study.

Outcome measures

Primary outcome

The primary outcome is clinical remission at the end of week 24. Patients achieving clinical remission should meet all of the following criteria:

1. No systemic symptoms (e.g. fever, fatigue, or weight loss).

2. No new onset of ischemic symptoms and signs.

3. Normal ESR level; if not achieved, the investigator should exclude other influencing factors, re-measure ESR after 1 week, and use the re-examined value in the analysis.

Patients achieving partial clinical remission must satisfy criteria (2) and one of (1) and (3).

Secondary outcomes

The secondary outcomes are listed below:

1. Time to clinical remission: from the date of randomization to the date of first documented clinical remission, assessed up to 24 weeks.

2. The mean dose of prednisone in the LEF intervention arm and placebo control arm at the end of 24 weeks.

3. Disease recurrence after achieving clinical remission (from week 25 to the end of week 52). Disease recurrence is defined as Kerr score ⩾2 or does not meet ⩾2 criteria of the standard for clinical remission.

4. Time to recurrence: from the beginning of achieving clinical remission to the date of the first documented disease recurrence, assessed up to 52 weeks.

5. Adverse events during follow-up.

6. Radiological changes (including CTA or MRA) at the end of 24 and 52 weeks compared with radiological features at baseline.

7. Clinical remission in individuals switched from the placebo control arm to LEF therapy after week 24, assessed up to 52 weeks.

Sample size estimation

We are assuming that 70% of cases will achieve clinical remission at the end of week 24 in the LEF intervention arm, and that 40% of cases will achieve clinical remission at the end of week 24 in the placebo control arm. Using the superiority test with a threshold of 10%, α = 0.025, β = 0.2, and assuming that 10% of patients will be lost to follow-up, the estimated sample size will be 58 people in each arm.

Dataset definitions

Modified intention-to-treat

Patients who undergo randomization and receive the intervention for ⩾12 weeks with one assessment of effect after 12 weeks should be included in modified intention-to-treat (mITT). mITT will be the primary analysis.

Full analysis set

All patients who undergo randomization and who receive at least one intervention with assessment of the effect after the intervention should be included in full analysis set (FAS). FAS will be the data set used for sensitivity analysis.

Per protocol set

Individuals who meet the inclusion criteria, do not meet the exclusion criteria, and complete the overall follow-up plan should be included in per protocol set (PPS).

For patients who drop out of the study due to a poor curative effect, the efficacy evaluation should be defined as ‘ineffective’.

For patients who suffer a severe adverse event and discontinue the intervention at any time during the study, the efficacy evaluation will be defined as ‘ineffective’.

Modified per protocol set

Modified per protocol set (mPPS) should include people who received an intervention for ⩾24 weeks with no major deviation of the protocol and who completed the visit at week 24. All the subjects should also satisfy the drug compliance ⩾80%.

Safety set

Persons who received the LEF/placebo intervention and had at least one safety analysis after the intervention should be included in the safety set (SS).

Missing values

Missing values of the primary endpoint visit could be replaced with the observed values of the closest evaluation visit. Missing values should be filled for mITT and FAS.

Statistical analyses

Statistical analyses will be done using SAS 9.2 (www.sas.com). A p value of ⩽0.05 (two-sided) will be considered significant. Also, 95% confidence intervals (CIs) will be used in the analysis. Baseline data will be analyzed based on FAS. Safety evaluation will be based on SS. FAS and mPPS will be used for the analyses of the primary outcome. The final conclusion will be based mainly on FAS analysis.

Continuous variables will be presented as the mean ± SD for data with a normal distribution, or as the median and interquartile range for data with a non-normal distribution. Categorical variables will be presented as numbers and percentages. Comparison of the overall loss to follow-up and the loss due to a severe adverse event between the LEF intervention arm and placebo control arm will be done using the χ² test or Fisher’s exact test. The primary outcome (clinical remission at week 24) will be compared using the χ² test. The 95% CI of the clinical remission rate at week 24 will be calculated using the Wilson procedure for the difference in the clinical remission rate between the LEF intervention arm and placebo control arm. The rate of disease recurrence, the time to recurrence, as well as the mean dose of prednisone will be calculated and compared between the LEF intervention arm and placebo control arm using the χ² test. Clinical remission in people who switched from the placebo control arm to the LEF intervention arm after week 24 to week 52 will be determined. The Kaplan–Meier method with log-rank analysis will be used to report and compare the disease recurrence rate in the LEF intervention arm and placebo control arm. Cox regression analysis will be used to compare the time to clinical remission and time to disease recurrence in the LEF intervention arm and placebo arm, with 95% hazard ratios being reported.

For safety analysis, the prevalence of an abnormal laboratory index and adverse events in the LEF intervention arm and placebo control arm will be estimated, respectively, and compared using the χ² test or Fisher’s exact test. The association of an abnormal laboratory index and adverse event with the investigational drug (LEF) will be evaluated.

Discussion

According to the 2021 ACR guideline for the management of TAK, oral GC combined with one or more DMARDs should be administrated to active patients to induce disease remission.¹¹ However, it is not recommended which DMARDs is the first-line choice. For years cyclophosphamide has been widely used as the first-line DMARD for TAK treatment in Chinese population, with clinical remission rate ranging 60–80%.^26,27 However, in Caucasian population, hemorrhagic cystitis related to cyclophosphamide is more commonly seen, which limited the application of cyclophosphamide.²⁸ The reproductive toxicity in childbearing women and opportunistic infections caused by cyclophosphamide is the biggest contradiction in clinical practice. It is important to find an alternative treatment with equivalent efficacy, but with less toxicity, to improve the life quality for TAK patients.

Except for rheumatoid arthritis, LEF has also been successfully used in lupus nephritis and vasculitis.^29–32 In giant cell arteritis, which is also a type of large-vessel vasculitis with similar characteristics to TAK, LEF treatment showed promising effects as a steroid-sparing agent and had lower relapse rate, lower cumulative GC dose, and good safety.³³ In our former prospective cohort studies, LEF has been proved to be effective in inducing disease remission in active TAK and shown satisfied safety including no menstrual disorders.^22–24 Thus, we propose that LEF would be a promising alternative treatment for TAK in Chinese population.

TAK is a rare disease with relative low incidence. Evidence of TAK treatment has come mostly from case–control studies and cohort studies. To our knowledge, this is the first randomized, double-blinded placebo-controlled trial to clarify the efficacy and safety of LEF in the treatment for active TAK. It is expected that LEF could induce maintain disease remission in most active TAK patients, and could also promote the clinical remission rate in patients who switch from placebo treatment to LEF treatment.