Adalimumab for Steroid Sparing in Giant-cell Arteritis
Adalimumab for Steroid Sparing in Giant-cell Arteritis
We designed a multicentre, randomised, double-blind, placebo controlled study to determine whether a short initial treatment with adalimumab added to a standardised programme of corticosteroid therapy in patients with newly diagnosed GCA would help to decrease corticosteroid requirement without increasing the relapse rate: HECTHOR (Humira* pour l'Epargne CorTisonique dans la maladie de HORton).
The study protocol was approved by the institutional review boards or committees for the protection of persons at the individual study sites. The study was conducted according to the current regulations of the International Conference on Harmonisation guidelines, and the principles of the Declaration of Helsinki. All patients provided written informed consent before participating in any protocol-specific procedures. Patients were enrolled from 16 June 2006 to 25 May 2010, and the last patient completed the study on 11 April 2011.
The study was conducted in 23 departments of rheumatology or internal medicine in France.
To be eligible for the study, patients had to be older than 50 years, have had a diagnosis of GCA according to the 1990 American College of Rheumatology Hunder criteria. If patients had started corticosteroids before randomisation, the dosage might be less than 1 mg/kg per day and it might have been initiated for less than 14 days before random assignment. The presence of typical findings of GCA on temporal biopsy was initially mandatory for inclusion in the trial. However, due to the slow progression of recruitment, the protocol was amended after the inclusion of 25 patients on 28 November 2007, and temporal artery biopsy was performed for all patients but its positivity was not mandatory to be eligible if the patients fulfilled Hunder criteria.
Patients were excluded if they had GCA-related visual symptoms (such as transient or permanent visual loss or diplopia) or had received anti-TNF or other forms of immunosuppressive therapy (such as methotrexate, azathioprine or other cytotoxic agents).
We excluded patients with: serious or chronic infections in the previous 30 days or who had required antibiotics in the previous 14 days; opportunistic infections; cancer or lymphoproliferative disorders within the 5 years before screening (with the exception of treated and cured squamous or basal cell carcinoma of the skin); a history of moderate to severe congestive heart failure or demyelinating disease; a recent stroke; current signs or symptoms of severe, progressive, or uncontrolled disease; evidence of active tuberculosis or latent tuberculosis (as defined by tuberculin skin test >5 mm or positive interferon gamma release assay); active chronic hepatitis B or C or HIV.
Adalimumab Regimen. Patients were randomly assigned in a 1:1 ratio to receive subcutaneous injection of adalimumab 40 mg or placebo at weeks 0, 2, 4, 6, 8, 10 in addition to prednisone (starting dose 0.7 mg/kg per day). The drug and placebo were indistinguishable in appearance. Randomisation was performed by use of a computer-generated list. Allocation to treatment group was performed by using a central randomisation procedure after facsimile verification of the correctness of inclusion criteria. Patients, investigators and study personnel were blinded to treatment assignments during the study. The time between randomisation and the first injection of the study drug was a maximum of 7 days.
Prednisone Regimen. Prednisone was tapered progressively according to a standardised protocol (Table 1). At each time point, prednisone could be decreased if patients had no clinical symptom and a C-reactive protein (CRP) level less than 15 mg/L. In cases of relapse (see definition below), the prednisone dose was increased to the immediately previous dose for 4 weeks and then further decreased according to the standardised schedule. In cases of active disease despite this protocol or in the case of relapse, the treatment schedule was left to the discretion of the physician in charge of the patient.
Additional Treatments. As some data suggested that low-dose aspirin decreases the rate of visual loss and cerebrovascular events in patients with GCA, all patients received low-dose aspirin (80–250 mg/day) during the first 3 months of the trial, with proton pump inhibitors if necessary. For preventing bone loss, all patients received a once-weekly administered bisphophonate dose associated with vitamin D (400UI/day) and calcium (1000 mg) supplementation.
The primary endpoint was the percentage of patients in remission with less than 0.1 mg/kg per day of prednisone at week 26. The secondary objectives were to assess the decrease in prednisone dose during the first 6 months of treatment, the proportion of patients who remained relapse free at 1 year, and the safety of a 10-week treatment with adalimumab in patients with GCA.
Remission was defined as the disappearance of clinical symptom and a CRP less than 15 mg/L. Relapse was defined as the reappearance of GCA-related clinical symptoms or an increase in CRP greater than 15 mg/L, at two time points at 1 week apart without any other obvious aetiology.
Sample Size. The study was designed with a planned sample size of 100 patients (50 in each group). According to a literature review, it was suspected that the percentage of patients achieving remission at 6 months with a prednisone dose below 0.1 mg/kg per day was approximately 40%. Adjunction of adalimumab would be considered as clinically meaningful if this proportion rose to 70% of patients. The power calculations were based on a bilateral χ test, with a type I error rate of 5%. To detect such a difference with a power of 80%, 42 patients in each arm was necessary. This number was increased to 50, with regard to the expected loss to follow-up rate. However, the rate of enrolment was slower than expected, and thus the sponsor asked for the termination of inclusions before the completion of the 100 planned patients in the study.
Primary Endpoint. The analysis was done according to the intention-to-treat principle. The proportion of patients maintaining remission at week 26 with a prednisone dose below 0.1 mg/kg per day was compared between the two groups using a logistic regression model with random effects at the centre level. If the prednisone dose at week 26 was not available, the patient was considered a non-responder to conform to the intention-to-treat principle. As a sensitivity analysis, a per-protocol analysis with only patients having received the planned treatment was performed.
Secondary Endpoints. The primary analysis was repeated for the proportion of patients maintaining remission at week 52.
The decrease in prednisone dose was compared between the two groups over the 26 and 52-week periods. This difference between groups was analysed using a linear model with random effects at the patient and centre levels. Inference was based on the restricted maximum likelihood solution. The model incorporates all available data for each patient into the analysis provided all patients had baseline data. It provides a likelihood function for the observed data from which treatment effects and other parameters can be estimated, with no additional steps being required to allow for missing data (under the hypothesis that missing data were missing at random). This model thus compared the mean adjusted difference at weeks 26 and 52 between the two groups
Time to first relapse was analysed using Kaplan–Meier survival. The time to first relapse was defined as the number of days between the date of first relapse and the date of inclusion. For those who did not relapse, time to first relapse was censored using the date of their final study visit. To assess difference, a linear rank test stratified on the centre was used.
All tests were two tailed; p values less than 0.05 were considered significant. Data analysis involved the use of SAS V.9.3 for Windows and R V.2.15.1.
Patients and Methods
Design
We designed a multicentre, randomised, double-blind, placebo controlled study to determine whether a short initial treatment with adalimumab added to a standardised programme of corticosteroid therapy in patients with newly diagnosed GCA would help to decrease corticosteroid requirement without increasing the relapse rate: HECTHOR (Humira* pour l'Epargne CorTisonique dans la maladie de HORton).
The study protocol was approved by the institutional review boards or committees for the protection of persons at the individual study sites. The study was conducted according to the current regulations of the International Conference on Harmonisation guidelines, and the principles of the Declaration of Helsinki. All patients provided written informed consent before participating in any protocol-specific procedures. Patients were enrolled from 16 June 2006 to 25 May 2010, and the last patient completed the study on 11 April 2011.
Setting
The study was conducted in 23 departments of rheumatology or internal medicine in France.
Participants
To be eligible for the study, patients had to be older than 50 years, have had a diagnosis of GCA according to the 1990 American College of Rheumatology Hunder criteria. If patients had started corticosteroids before randomisation, the dosage might be less than 1 mg/kg per day and it might have been initiated for less than 14 days before random assignment. The presence of typical findings of GCA on temporal biopsy was initially mandatory for inclusion in the trial. However, due to the slow progression of recruitment, the protocol was amended after the inclusion of 25 patients on 28 November 2007, and temporal artery biopsy was performed for all patients but its positivity was not mandatory to be eligible if the patients fulfilled Hunder criteria.
Patients were excluded if they had GCA-related visual symptoms (such as transient or permanent visual loss or diplopia) or had received anti-TNF or other forms of immunosuppressive therapy (such as methotrexate, azathioprine or other cytotoxic agents).
We excluded patients with: serious or chronic infections in the previous 30 days or who had required antibiotics in the previous 14 days; opportunistic infections; cancer or lymphoproliferative disorders within the 5 years before screening (with the exception of treated and cured squamous or basal cell carcinoma of the skin); a history of moderate to severe congestive heart failure or demyelinating disease; a recent stroke; current signs or symptoms of severe, progressive, or uncontrolled disease; evidence of active tuberculosis or latent tuberculosis (as defined by tuberculin skin test >5 mm or positive interferon gamma release assay); active chronic hepatitis B or C or HIV.
Randomisation and Intervention
Adalimumab Regimen. Patients were randomly assigned in a 1:1 ratio to receive subcutaneous injection of adalimumab 40 mg or placebo at weeks 0, 2, 4, 6, 8, 10 in addition to prednisone (starting dose 0.7 mg/kg per day). The drug and placebo were indistinguishable in appearance. Randomisation was performed by use of a computer-generated list. Allocation to treatment group was performed by using a central randomisation procedure after facsimile verification of the correctness of inclusion criteria. Patients, investigators and study personnel were blinded to treatment assignments during the study. The time between randomisation and the first injection of the study drug was a maximum of 7 days.
Prednisone Regimen. Prednisone was tapered progressively according to a standardised protocol (Table 1). At each time point, prednisone could be decreased if patients had no clinical symptom and a C-reactive protein (CRP) level less than 15 mg/L. In cases of relapse (see definition below), the prednisone dose was increased to the immediately previous dose for 4 weeks and then further decreased according to the standardised schedule. In cases of active disease despite this protocol or in the case of relapse, the treatment schedule was left to the discretion of the physician in charge of the patient.
Additional Treatments. As some data suggested that low-dose aspirin decreases the rate of visual loss and cerebrovascular events in patients with GCA, all patients received low-dose aspirin (80–250 mg/day) during the first 3 months of the trial, with proton pump inhibitors if necessary. For preventing bone loss, all patients received a once-weekly administered bisphophonate dose associated with vitamin D (400UI/day) and calcium (1000 mg) supplementation.
Outcomes and Measurements
The primary endpoint was the percentage of patients in remission with less than 0.1 mg/kg per day of prednisone at week 26. The secondary objectives were to assess the decrease in prednisone dose during the first 6 months of treatment, the proportion of patients who remained relapse free at 1 year, and the safety of a 10-week treatment with adalimumab in patients with GCA.
Remission was defined as the disappearance of clinical symptom and a CRP less than 15 mg/L. Relapse was defined as the reappearance of GCA-related clinical symptoms or an increase in CRP greater than 15 mg/L, at two time points at 1 week apart without any other obvious aetiology.
Statistical Analysis
Sample Size. The study was designed with a planned sample size of 100 patients (50 in each group). According to a literature review, it was suspected that the percentage of patients achieving remission at 6 months with a prednisone dose below 0.1 mg/kg per day was approximately 40%. Adjunction of adalimumab would be considered as clinically meaningful if this proportion rose to 70% of patients. The power calculations were based on a bilateral χ test, with a type I error rate of 5%. To detect such a difference with a power of 80%, 42 patients in each arm was necessary. This number was increased to 50, with regard to the expected loss to follow-up rate. However, the rate of enrolment was slower than expected, and thus the sponsor asked for the termination of inclusions before the completion of the 100 planned patients in the study.
Primary Endpoint. The analysis was done according to the intention-to-treat principle. The proportion of patients maintaining remission at week 26 with a prednisone dose below 0.1 mg/kg per day was compared between the two groups using a logistic regression model with random effects at the centre level. If the prednisone dose at week 26 was not available, the patient was considered a non-responder to conform to the intention-to-treat principle. As a sensitivity analysis, a per-protocol analysis with only patients having received the planned treatment was performed.
Secondary Endpoints. The primary analysis was repeated for the proportion of patients maintaining remission at week 52.
The decrease in prednisone dose was compared between the two groups over the 26 and 52-week periods. This difference between groups was analysed using a linear model with random effects at the patient and centre levels. Inference was based on the restricted maximum likelihood solution. The model incorporates all available data for each patient into the analysis provided all patients had baseline data. It provides a likelihood function for the observed data from which treatment effects and other parameters can be estimated, with no additional steps being required to allow for missing data (under the hypothesis that missing data were missing at random). This model thus compared the mean adjusted difference at weeks 26 and 52 between the two groups
Time to first relapse was analysed using Kaplan–Meier survival. The time to first relapse was defined as the number of days between the date of first relapse and the date of inclusion. For those who did not relapse, time to first relapse was censored using the date of their final study visit. To assess difference, a linear rank test stratified on the centre was used.
All tests were two tailed; p values less than 0.05 were considered significant. Data analysis involved the use of SAS V.9.3 for Windows and R V.2.15.1.
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