Short-Term Efficacy & Safety of Leflunomide (Arava) in the Treatment of Active RA in Everyday Clinical Use

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Short-Term Efficacy and Safety of Leflunomide in the Treatment of Active

Rheumatoid Arthritis in Everyday Clinical Use:

Open-Label, Prospective Study

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Clin Drug Invest 24(2):103-112, 2004.

Posted 03/16/2004

Abstract and Introduction

Abstract

Objective: To determine the efficacy and safety profile of 6-month

treatment with leflunomide 20mg daily in patients with acute rheumatoid

arthritis (RA) receiving treatment from 197 office-based rheumatologists

in France.

Methods: This open-label, prospective, multicentre study included 378

ambulatory RA patients who received leflunomide at a loading dose of

100mg daily on days 1–3, followed by 20mg daily for 6 months. The

primary efficacy endpoint was a >/=20% response according to the

American College of Rheumatology criteria (ACR 20) after 6 months.

Secondary efficacy criteria were a >/=50% response (ACR 50) and a >/=70%

response (ACR 70), as well as disease activity score (DAS28) responses.

Results: Among the 407 selected patients, 378 patients were included in

the study, all of whom were treated with leflunomide. Female patients

made up 78.6% of the study population; the mean age was 57.7 ± 12.0

years, and the mean disease duration was 9.7 ± 8.5 years. At 6 months,

the ACR 20 response rate was 48.2%. ACR 50 and 70 response rates were

25.3% and 11.7%, respectively. According to the DAS28, 21.8% of patients

had a good response, 39.9% a moderate response, and 38.2% were

non-responders. The DAS28 response rate was thus 61.8%. Mean

improvements in tender joint count were –5.6 ± 7.4 (from baseline of

12.2 ± 6.7), in swollen joint count were –4.2 ± 5.7 (from baseline of

9.8 ± 5.8), and in investigator's global assessment of RA disease

activity were –20.2 ± 25.1 (from baseline of 51.6 ± 17.1).

Treatment-related adverse events caused 15.9% of patients to discontinue

the study prematurely. Serious adverse events possibly related to

therapy were reported in 2.4% of patients.

Conclusions: This 6-month study carried out under daily routine practice

conditions in a typical sample of RA patients showed a favourable

efficacy and safety profile for leflunomide 20mg daily. The study

confirms the findings of the earlier phase II and III study programme in

more selected patient samples.

Introduction

The cornerstones of modern pharmacological treatment of rheumatoid

arthritis (RA) involve the use of nonsteroidal anti-inflammatory drugs

(NSAIDs) as well as disease-modifying antirheumatic drugs (DMARDs).[1]

While the former are used to control pain caused by acute

inflammation,[2] DMARDs have been shown to slow down the chronic

destructive biological processes that are the driving force behind

persistent inflammation.[3] The major limitation of currently employed

DMARDs is their limited drug-survival span either because of toxicity or

because of weaning efficacy,[4] and thus an array of these drugs is

needed to control pain and inflammation during the course of disease.

Leflunomide is a new immunosuppressant and anti-inflammatory DMARD that

has already been approved in the US, Central and South America,

Australia and the European Union.[5] It was marketed in France in

September 2000.

The immunomodulatory effects of leflunomide are exerted via its active

metabolite A771726, which inhibits dihydroorotate dehydrogenase and

tyrosine kinase activity in actively dividing lymphocytes. An additional

inhibitory effect on B-cell proliferation and the production of

antibodies contributes to the immunosuppressive action of the drug.[6]

The phase II and III clinical trial programme involving more than 1300

patients with active RA demonstrated therapeutic efficacy and safety of

leflunomide not only compared with placebo,[7] but also in direct

comparisons with methotrexate[8,9] and sulfasalazine.[10,11]

The present trial was conducted as an open-label post-registration study

to assess whether the efficacy and safety results obtained in the

controlled clinical trial setting with leflunomide in adult RA at the

standard dosage of 20 mg/day for 6 months can be extra-polated to

everyday practice. The American College of Rheumatology (ACR) 20

response rate (>/=20%) was defined as the primary efficacy endpoint,

while the ACR 50 (>/=50%) and ACR 70 (>/=70%) response rates and the

disease activity score (DAS28) were assessed as secondary endpoints.[12]

Methods

Subjects

Male and female patients >/=18 years of age were included by private

practice rheumatologists if they had active RA according to the ARA 1987

criteria,[13] with a score between 2 and 5 on a 5-point Likert activity

scale.

Patients meeting one or more of the following criteria were excluded

from the study:

1.

Intra-articular or parenteral corticosteroid treatment in the 4

weeks prior to inclusion (baseline visit).

2.

Oral corticosteroid treatment with a non-stable dosage or a

dosage higher than 10 mg/day of a prednisone equivalent, or treatment

with a DMARD in the 2 weeks prior to inclusion.

3.

Contraindications to leflunomide: hypersensitivity to

leflunomide; serious immunodeficiency; serious medullary disorder or

anaemia (haemoglobin <10 g/dL), leucopenia (white blood count

<3000/mm3), and/or neutropenia (<1500/mm3) or thrombocytopenia (<100

000/mm3) that was not caused by RA; serious infections; moderate to

severe renal failure (creatinine clearance according to Cockroft's

formula </=50 mL/min); hepatic insufficiency (bilirubin, albumin,

aspartate aminotransferase [AST] or alanine aminotransferase [ALT] >/=3

times upper limit of normal); severe hypoproteinaemia (e.g. nephrotic

syndrome [hypoalbuminaemia <3.3 g/dL]); pregnant or breastfeeding women,

or women of childbearing age not using adequate contraception prior to

enrolment.

Study Design

This was a 6-month, multicentre, open-label, prospective, phase IV study

that was conducted by private rheumatologists practising in 197

rheumatology offices throughout France. The sample size was calculated

based on the hypothesis that leflunomide is equally effective in the

office-based setting as in the clinical setting.

The Independent Ethics Committee of Hôpital Cochin, Paris, France,

approved the protocol, and the study was performed according to the

guidelines of the Declaration of Helsinki. Written informed consent was

obtained from all patients.

The clinical trial included five visits: screening, baseline (1–4 weeks

after the screening visit), and follow-up visits after 1, 3 and 6 months

(end of study), respectively, or before in the case of a premature

withdrawal. Laboratory tests (red and white cell count, platelet count,

blood pregnancy test, ALT, AST, serum creatinine, albumin and renal

function) were performed at the baseline visit and at visits 3, 4 and 5.

Before treatment with the study medication was initiated, a washout

period of 2 weeks was required in the case of prior treatment with

DMARDs. If a patient was treated with intra-articular or parenteral

corticosteroids, a washout period of 4 weeks was required.

After oral administration of an initial loading dose of leflunomide

100mg daily for the first 3 days of treatment, study patients received

an oral maintenance dosage of leflunomide 20mg daily for 6 months. If an

increase in ALT levels twice the upper limit of normal occurred and

persisted, according to the investigator's discretion the dosage was

reduced to 10mg daily. In any case, if ALT levels persisted between two

and three times the upper limit of normal (ULN) for more than 2 weeks,

leflunomide treatment was stopped according to the recommendations of

the manufacturer.

Stable doses of NSAIDs and oral corticosteroids as concomitant

medication were allowed during the study period. Intra-articular

corticosteroids were allowed, with the exception of injections taking

place in the 4 weeks prior to visits 3, 4 or 5. Other DMARDs, any other

investigational drug and live vaccines were not allowed.

Coadministration of drugs also metabolised by cytochrome P450-2C9

(CYP2C9) [e.g. phenytoin, warfarin and salbutamol] and other medications

interacting with the metabolism of leflunomide (e.g. cholestyramine and

charcoal) were avoided.

Efficacy and Safety Assessments

At each study visit the ACR 20 response rate (the primary efficacy

criterion) and the ACR 50 and ACR 70 response rates were assessed:

tender joint count (TJC; 28 joints evaluated[14]), swollen joint count

(SJC), investigator's and patient's global evaluation of health (on a

visual analogue scale [VAS]), patient evaluation of pain (on a VAS),

functional index (Health Assessment Questionnaire [HAQ]),[15] and

erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP).

The DAS28[16] was calculated based on the SJC, TJC, ESR and general

health scale (GH). The disease activity was considered to be low if the

DAS28 score was </=3.2, as moderate if the score was >3.2 and </=5.1,

and as high in the case of a DAS28 score >5.1. The duration of morning

stiffness was assessed by asking the patient to estimate the time

required after waking up to be able to perform usual everyday

activities, and recorded in minutes. For the assessment of pain by the

patient, a VAS using a 100mm horizontal scale (0 = no pain; 100mm =

maximum, non-bearable pain) was used to record overall pain, pain at

rest and pain on movement. Safety and tolerability were assessed on the

basis of adverse events, physical examination, weight and blood

pressure, laboratory tests (red and white cell counts and platelet

count, serum ALT, serum pregnancy tests).

The term adverse event covered any sign, symptom, syndrome or illness

observed by the investigator or reported by the patient that developed

or worsened during the period of observation in the clinical study.

Severity (mild, moderate or severe) was rated according to the

investigator's assessment. An adverse event was classified as serious if

it met any of the following criteria: resulted in death, was

life-threatening, required inpatient hospitalisation or prolongation of

existing hospitalisation, resulted in persistent or significant

disability or incapacity, was a congenital anomaly or birth defect or

was otherwise an important medical event. All adverse events were

classified according to whether they occurred during the pretreatment,

on-treatment or post-treatment period.

Compliance of study patients was assessed by tablet counts and patients

were questioned about medication intake. It was rated as good if the

intake was >/=80%.

Statistical Considerations

The sample size was calculated according to the ACR 20 responses

observed in clinical phase II and III studies. Presuming an ACR 20

response rate of 55% under study treatment, 440 patients were required

with a two-sided ? risk of 5% and a power of 85% in order to obtain the

minimum acceptable ACR 20 response rate of 47%.

According to the predefined statistical analysis plan, the statistical

analyses of primary and secondary criteria were performed descriptively

and were interpreted in an explorative way. The statistical threshold

for the statistical tests carried out during the exploratory analyses

was set at 5%. Quantitative variables were analysed (distribution) by

their frequency, mean, standard deviation, standard deviation to the

mean, median, first and third quartiles, extreme values (minimum and

maximum) and missing data. Qualitative variables were analysed

(allocation) by the frequency and percentage of each of the ways of

answering, as well as the missing data that was integrated into the

calculation of the percentage.

The intention-to-treat (ITT) population consisted of all screened

patients who took at least one dose of study medication. The

per-protocol (PP) population consisted of all patients from the ITT

population excluding patients withdrawn from treatment. The primary

analysis consisted of an ITT analysis of the ACR 20 using the last

observation carried forward (LOCF) method (the last available evaluation

was to be taken into account in the analysis). The ACR 20, 50 and 70

responses rates, respectively, at final evaluation and their 95%

two-sided confidence intervals (CIs) were calculated. An ancillary PP

analysis was also done for the primary criterion in order to assess the

soundness of the ITT analysis.

The safety analysis was performed in the ITT population. Adverse events

were considered to be related to the treatment if they were judged so by

the investigator. The analysis of data was performed with the

statistical software package SAS 6.0 (SAS Institute Inc., Cary, NC, USA).

Results

Patients

From 197 practices, a total of 407 patients were screened for

eligibility. Twenty-nine patients were selected but not included into

the study for other reasons; they did not receive study medication. Of

the 378 treated patients, 288 patients (76.2%) completed the study, and

90 patients (23.8%) were withdrawn prematurely. A study flow chart

showing patient inclusion and patient baseline demographics are shown in

figure 1 and table I, respectively. During the study period, 232

patients (61.4%) received concomitant corticosteroid therapy.

Figure 1. Study flow chart.

Among the 378 treated patients, 352 patients (93.1%) were treated with

leflunomide 20 mg/day for the whole study period (mean 153 ± 53.1 days).

Twenty-six patients (6.9%) had a dosage decrease during the study. Lack

of efficacy was mentioned as a reason for withdrawal in 16 patients (17.8%).

In the case of early discontinuation (90 patients), the study medication

was taken for the following time periods: 6% of patients <1 week, 23%

between 1 week and 1 month, 17% between 1 and 2 months, 23% between 2

and 3 months, 13% between 3 and 4 months, 12% between 4 and 5 months,

and 6% between 5 and 6 months.

The study population at baseline visit consisted of 297 women (78.6%)

and 81 men (21.4%). The mean ± SD age of patients was 57.7 ± 12.0 years

(range 21–82 years). Overall, 256 patients (67.7%) were <65 years of age

and 122 patients (32.3%) were >65 years of age. Bodyweight was available

at baseline for 374 patients: the mean was 67.8 ± 14.3kg (range 36–45kg).

At baseline, the RA had been present for more than 2 years in 80.4% of

patients. Patients had a mean disease duration of 9.7 ± 8.5 years, and

87.3% had already been treated with a DMARD. Before inclusion into the

study patients had received on average 2.3 ± 1.6 DMARD treatments (range

1–9). The most frequently reported previous DMARD treatments were

methotrexate (54%), gold derivatives (47.4%) and hydroxychloroquine

(41.5%). The mean duration of morning stiffness at baseline was 1.5 ±

2.0 hours. The mean SJC was 9.8 ± 5.8 and the mean TJC was 12.2 ± 6.7.

The disease activity according to the DAS28 at baseline was low (DAS28

</=3.2) in two patients (0.5%), moderate (3.2 < DAS28 </= 5.1) in 124

patients (32.8%), and high (DAS28 >5.1) in 238 patients (63.0%). The

DAS28 was missing for 14 patients (3.7%). The mean investigator's global

assessment of disease activity on a VAS was 51.6mm.

Among the 378 treated patients, 360 patients (95.2%) showed good

compliance with leflunomide treatment, nine patients (2.4%) showed poor

compliance (<80%), and in nine patients (2.4%) compliance was not assessed.

Efficacy

At endpoint in the ITT population, 177 patients responded to leflunomide

treatment according to the ACR 20 criteria, and 190 patients (51.8%)

were non-responders (figure 2). The data of 11 patients were missing. In

the PP population, the analysis of the ACR 20 response rate in 163

patients led to similar results, with an ACR 20 response of 49%.

Figure 2. Percentage of responders and non-responders to 6-month

treatment with leflunomide 20mg daily according to American College of

Rheumatology (ACR) criteria. ACR 20 = >/=20% response; ACR 50 = >/=50%

response; ACR 70 = >/=70% response.

According to the ACR 50 criteria, 93 patients (25.3%; CI 21.0–30.1) were

responders and 274 patients (74.7%) were non-responders. According to

the ACR 70 criteria, 43 patients responded and 325 patients (88.3%) were

non-responders.

Disease activity according to the DAS28 was assessed from the data of

353 patients. The data for 25 patients were not available for follow-up

evaluation. 218 patients were responders: 77 patients (21.8%) had a good

response and 141 patients (39.9%) had a moderate response. 135 patients

(38.2%) were non-responders. Table II shows the DAS28 score in the ITT

population at visits 2–5 during the study and at end-point. The course

of the rheumatoid factor during the study period is presented in table III.

The analyses of the RA disease assessment criteria revealed an

improvement in all criteria between visit 2 and visit 5, and between

visit 2 and end-point. The data are presented in table IV. Biological

signs (CRP and ESR) were reduced with leflunomide treatment. The TJC and

SJC decreased according to both patients' and investigators' judgements.

The HAQ scores will be presented in a separate paper dealing with the

patient's quality of life under leflunomide treatment.

Safety

Adverse Events. Adverse events were reported in 270 of 378 patients

(71.4%). In 186 patients (49.2%), at least one possibly drug-related

adverse event was reported. An overview of all adverse events is

presented in table V.

The most frequently reported adverse events were diarrhoea, alopecia,

hypertension and increases in ALT. In most cases the intensity of events

was mild (132 patients; 34.9%) or moderate (191 patients; 50.5%). It was

classified as severe in only 63 patients (16.7%).

Adverse events resulting in discontinuation of therapy with leflunomide

were reported in 60 patients (15.9%). The most frequently reported

adverse events resulting in discontinuation of leflunomide therapy

affected the digestive system (6.9%) and the skin and appendages (3.7%).

Notably diarrhoea, nausea, hypertension and rash occurred early during

treatment with leflunomide. Most of these events were reported during

the first month of treatment.

Serious Adverse Events. Overall, 34 patients (9.0%) reported at least

one serious adverse event. Among these patients, two deaths occurred

that were not related to leflunomide (one cardio-respiratory arrest and

one cerebral haemorrhage). Nine of these serious adverse events (2.4%)

were possibly related to leflunomide therapy: ALT increases (4),

persisting fever (1), cystitis leading to hospitalisation (1), acute

renal failure following diarrhoea (1), Gougerot-Sjögren's syndrome (1),

and flare in RA (1).

Laboratory Safety Data, Blood Pressure and Bodyweight. A decrease in

haemoglobin level was noted in 14 patients (4.6%), but only three (0.8%)

of them had a value <10 g/dL at endpoint. Only one patient had a

platelet count <120 000/mm3; however, this patient recovered.

Clinically noteworthy increases in liver enzymes were observed for the

ALT liver test in 82 patients. Fifty-six patients (14.8%) had ALT values

between 1.2 and two times the ULN at least once during the study period,

19 patients (5.0%) between two and three times the ULN, and seven

patients (1.9%) more than three times the ULN. In the group of seven

patients with ALT values more than three times the ULN, all but one

returned to normal or decreased significantly after discontinuation of

leflunomide. One patient received a dosage reduction to 10mg daily

before the study medication was discontinued because of persisting ALT

values between 1.5 and twice the ULN.

AST values were normal at baseline and endpoint for the majority of

study subjects (92.3%). Only 19 patients with normal values at baseline

presented with increased AST liver function tests at study end. Other

clinical chemistry and urinalysis findings were without clinical

relevance. A slight increase in blood pressure was observed. The mean

weight was relatively stable.

Discussion

This study investigated, for the first time, the efficacy and safety

profile of leflunomide 20mg daily in ambulatory RA patients in typical

settings. This is of importance, as the existing body of evidence of

leflunomide therapy is mainly derived from the clinical development

programme. The efficacy and safety of leflunomide monotherapy has been

documented in a large phase II dose-finding study[7] and in several

large randomised, double-blind, comparative multicentre

studies.[9-11,18] However, it is not clear if these results obtained in

controlled clinical settings are fully transferable into an ambulatory

setting in daily practice. The present study fills this gap.

Methodological Considerations

For the present phase IV trial we chose an open-label study design with

an unselected typical patient sample recruited by office-based

rheumatologists. The patient characteristics in the present study

differed from those of the previous phase III trials[9,10,18] in terms

of longer disease duration, a higher percentage of previous DMARD use,

and less active disease, but with larger variations. This ensured that

all types of patients with a broad variety of concomitant diseases or

medications were investigated, which makes the results suitable for

extrapolation to daily routine practice.

However, the interpretation of results obtained from open-label,

non-controlled studies requires consideration of certain limitations.

Firstly, the absence of a placebo control group renders the

interpretation of the size of the placebo effect and the relative

efficacy compared with other treatments difficult. Secondly, as the

patients were not randomly assigned to the study treatment a certain

kind of selection bias cannot be avoided.

Furthermore, for the interpretation of safety results it has to be taken

into account that the causality of a drug in relation to an adverse

event is difficult to assess without a control group. Nevertheless, a

comparison of the results of our present study with controlled studies

is useful as the investigated patient sample is closer to real-life

practice. Recent systematic comparisons of observational studies with

randomised controlled trials confirmed the principal validity of the

results of a well designed uncontrolled study.[19,20]

Efficacy

The present study adds important information to the literature, as this

is the first study to quantify the effects of leflunomide treatment in

an office-based physician setting. As the study was initiated only 4

months after the introduction of leflunomide into clinical practice, it

can be expected that the loading dose according to the product

information was applied in almost all patients. According to the ACR 20

criteria we observed a response rate of 48%. This rate was lower than

expected compared with the results obtained in previous phase II and III

trials, which reported ACR 20 response rates of 60%[7] and 55%.[10,11]

When these results are compared with the findings of randomised,

placebo-controlled studies with endpoints after 6 months in a clinical

setting,[7,10,11] the responses in the present trial are slightly lower.

Different patient characteristics and a more heterogenous group of

patients with longer disease duration, as described above, might explain

the lower response rate. The washout period of 2 weeks for previous

DMARD treatment before study inclusion was rather short. Thus, compared

with the clinical studies, the RA disease activity in the present study

patients was lower, which could contribute to the lower response rate.

In the present population the mean disease duration was 9.7 years,

compared with 7 years in the study performed by Smolen et al.[10]

Therefore it is possible that patients with shorter disease duration

might have a better and quicker response after initiation of leflunomide

treatment. The DAS28, a validated instrument that is independent of

disease duration,[14] continuously improved during the study period,

confirming the benefits of leflunomide treatment in this population. The

complementary analysis of the PP population excluding patients withdrawn

from the study revealed an ACR 20 response of 57.6%, which corresponds

with the ACR 20 response rates of 55% reported in comparable studies by

Smolen et al.[10] and et al.[11] In all previous studies patients

were followed up by hospital rheumatologists and might have benefited –

as a result of study stipulations – from a more frequent and closer

clinical monitoring and assessment of disease activity compared with

patients in an ambulatory setting. This might lead to some bias and

could explain the slightly lower responses observed in the ITT population.

Safety

The present study performed in an office-based physician setting

confirms the beneficial safety profile of leflunomide observed in the

large phase II and III trials. The overall frequency of adverse events

resulting in discontinuation of therapy was 15.9%, which is slightly

higher than in the study performed by Smolen et al.[10] (14%), but lower

compared with the results of Emery et al.[18] (19%) and Strand et al.[9]

(22%).

This study confirms that the adverse events diarrhoea, alopecia,

hypertension and increases in ALT are known and expected adverse effects

which appear in the labelling for leflunomide. The intensity of most

events was slight or moderate. Because of the antiproliferative effect

of leflunomide on intestinal tissues, diarrhoea is not unusual; however,

this effect usually stops within 1 or 2 months. The frequency of

clinically noteworthy liver enzyme increases (>3 ULN 1.9%) was

comparable to previous studies performed by Strand et al. (4.4%)[9] and

Emery et al. (2.4%).[18] Lack of efficacy was mentioned as a reason for

withdrawal in 17.8% of patients, which is higher than the phase III

trials.[9,11] This finding is not unexpected and may be related to the

fact that the patients included in our study were less preselected than

those in the randomised, controlled clinical settings. On the other hand

this might reflect a compliance problem as medication intake is

regularly more difficult to control in a private practice setting.

However, many RA patients have to discontinue DMARD treatment because of

weaning effectiveness or because of adverse events.[21,22] These

patients might be candidates for combination therapies allowing a lower

dosage regimen of the individual DMARDs, which might reduce potential

drug toxicity. Preliminary study results have revealed promising

benefits for combination therapy of leflunomide and methotrexate.[23]

Severity and overall incidence of adverse effects in the present setting

were not higher compared with randomised, controlled studies.[9,10,18]

Conclusion

In a typical ambulatory RA patient sample, 6-month treatment with

leflunomide 20mg was effective and well tolerated. Compared with the

characteristics of patients in the phase II and III clinical trial

programme, patients in the present investigation had a longer disease

duration, were more likely to have previously used other DMARDs, and had

less active disease. Nevertheless, the efficacy and safety outcomes were

similar, confirming the favourable benefit : risk ratio of leflunomide

under daily practice conditions. Further research in order to compare

the efficacy and safety of leflunomide with methotrexate and

sulfasalazine in ambulatory RA patients should be implemented.

Minh Nguyen; Marmar Kabir; Philippe Ravaud

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Acknowledgements

We would like to acknowledge the cooperation and commitment of all the

local general physicians and their staff without whom the present study

would not have been possible.

Funding Information

Aventis Pharma, Paris, France, funded the study.

Reprint Address

Dr Minh Nguyen, Clinique de Rhumatologie, Hôpital Cochin, 27 rue du

Faubourg Saint Jacques, 75674 Paris Cedex 14, France. E-mail:

secretariat.dougados@...

Minh Nguyen1, Marmar Kabir2, Philippe Ravaud1

1René Descartes University, Institute of Rheumatology, Cochin Hospital,

Paris, France, 2Department of Biostatistics, Aventis Laboratories,

Paris, France

Disclosure: The authors have provided no information on conflicts of

interest directly relevant to the content of this study.