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出境医 / 临床实验 / Giant Cell Arteritis: Comparison Between Two Standardized Corticosteroids Tapering (CORTODOSE)

Giant Cell Arteritis: Comparison Between Two Standardized Corticosteroids Tapering (CORTODOSE)

Study Description
Brief Summary:

Corticosteroid therapy has always been the standard treatment for giant cell arteritis (GCA), with very good initial clinical efficacy but a high relapse rate when it declines.

The target population of this condition, often elderly, is particularly exposed to the numerous undesirable effects of corticosteroid therapy, and this especially as its duration lengthens with the re-increases of doses according to relapses: metabolic complications, osteo-muscular , infectious or neuropsychiatric.

Investigators propose to compare prospectively the results of a "conventional" corticosteroid regimen as recommended by European societies, to those of a "lighter and / or shorter" scheme, inspired by recent North American trials. , including the largest prospective global study in the field. Investigators hypothesize non-inferiority of the lightened regimen for relapse rate without relapse at S52, but with a decrease in treatment-related adverse events whose cumulative doses should be lower.

Investigators therefore plan to include prospectively over 3 years 150 patients, 75 for each of the two arms, with a newly diagnosed ACG. A randomization of the treatment arm will be performed and a predefined pattern of cortisone adapted to body weight will be given to the patient. Relapse rates, maintenance of remission, cumulative doses of cortisone and adverse effects of treatment will be analyzed at the 52nd week of the introduction of corticosteroid therapy. An interim analysis is planned at S28.


Condition or disease Intervention/treatment Phase
Giant Cell Arteritis Drug: Corticosteroids for Systemic Use Phase 3

Detailed Description:

Treatment of giant cell arteritis (GCA) relies on the use of glucocorticoids (GC), with a very good clinical response at treatment initiation. However, relapses at GC tapering are frequent. GCA population is elderly, frequently over 80 years, and is especially affected by GC-related side effects, that increase proportionally with treatment duration. Thus, metabolic, musculo-skeletal, infectious or neuro-psychiatric complications are frequent during prolonged GC use.

After GC introduction, gradual tapering is scheduled, provided the disease remains clinically and biologically controlled. In France, guidelines recommend tapering GC on an 18-24 months timeframe, while other countries, such as the USA, usually taper GC over a shorter period, often 6-8 months. Few comparative data exist on the relapse rates or the GC-related side effects in both settings. In this prospective multicenter study, two GC-tapering schedules are planned: patients in one arm (short treatment) will be treated for 28 weeks, while patients in the second arm will be treated for 52 weeks. Each starting dose of GC and tapering doses will be adapted to body weight. The primary endpoint is to compare the remission rate without relapse at W52 between the two groups and the secondary endpoints are: 1) cumulative GC doses at W52; 2) GC-related side effects and 3) number of relapses (minor and severe) in both arms at W52.

The results of this study might considerably modify future French clinical practice if investigators confirm that a shorter GC treatment does not significantly impact the disease course while reducing GC-related side effects.

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 150 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized, Controled, Open Label Trial: Comparison Between Two Standardized Corticosteroids Tapering, Respectively Short (North American) and Long (European), in Giant Cell Arteritis
Estimated Study Start Date : November 5, 2020
Estimated Primary Completion Date : November 2023
Estimated Study Completion Date : January 2027
Arms and Interventions
Arm Intervention/treatment
Experimental: Short tapering corticosteroids
Corticosteroid taper over 28 weeks
 Drug: Corticosteroids for Systemic Use

Corticosteroids tapering over 28 weeks:

J0 = 0,7 mg/kg S2 = 0,6 mg/kg S4 = 0,5 mg/kg S6 = 0,4 mg/kg S8 = 0,3 mg/kg S10 = 0,25 mg/kg S12 = 0,2 mg/kg S14 = 0,15 mg/kg S16 = 0,15 mg/kg S20 = 0,1 mg/kg S24 = 0,05 mg/kg S28 = 0 mg/kg

Corticosteroids tapering over 52 weeks:

J0 = 0,7 mg/kg S2 = 0,6 mg/kg S4 = 0,6 mg/kg S6 = 0,5 mg/kg S8 = 0,4 mg/kg S10 = 0,3 mg/kg S12 = 0,25 mg/kg S14 = 0,2 mg/kg S16 = 0,175 mg/kg S20 = 0,15 mg/kg S24 = 0,125 mg/kg S28 = 0,01 mg/kg S32 to S52: - 1mg per month
Active Comparator: Long tapering corticosteroids
Corticosteroid taper over 52 weeks
 Drug: Corticosteroids for Systemic Use

Corticosteroids tapering over 28 weeks:

J0 = 0,7 mg/kg S2 = 0,6 mg/kg S4 = 0,5 mg/kg S6 = 0,4 mg/kg S8 = 0,3 mg/kg S10 = 0,25 mg/kg S12 = 0,2 mg/kg S14 = 0,15 mg/kg S16 = 0,15 mg/kg S20 = 0,1 mg/kg S24 = 0,05 mg/kg S28 = 0 mg/kg

Corticosteroids tapering over 52 weeks:

J0 = 0,7 mg/kg S2 = 0,6 mg/kg S4 = 0,6 mg/kg S6 = 0,5 mg/kg S8 = 0,4 mg/kg S10 = 0,3 mg/kg S12 = 0,25 mg/kg S14 = 0,2 mg/kg S16 = 0,175 mg/kg S20 = 0,15 mg/kg S24 = 0,125 mg/kg S28 = 0,01 mg/kg S32 to S52: - 1mg per month
Outcome Measures
Primary Outcome Measures :
  1. Patient in complete remission over a follow up of 52 weeks, without relapse [ Time Frame: Baseline up to 52 weeks ]

Secondary Outcome Measures :
  1. First relapses rate at S28 and S52 [ Time Frame: Weeks 28 and 52 ]
  2. Second relapses rate at S28 and S52 [ Time Frame: Weeks 28 and 52 ]
  3. Delay between first and second relapses [ Time Frame: Baseline up to 52 weeks ]
  4. Cumulative and the average dose of prednisone used [ Time Frame: Weeks 28 and 52 ]
  5. Number of patient with corticosteroids dependence at week 52 [ Time Frame: Baseline up to 52 weeks ]
  6. Safety according CTCAE v5.0 [ Time Frame: Baseline up to 52 weeks ]

Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   50 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age ≥ 50 years

  • Patient with temporal arteritis giant cell match 2 of the 4 criteria of the American College of Rheumatology (ACR) that given :

    • a temporal artery biopsy compatible with a diagnosis of CAG or
    • an abdominal thoracic aortitis diagnosed by Angio CT, MR angiography or PET scanner or
    • Echo Doppler compatible with a diagnosis of CAG
  • Oral corticosteroid treatment started up to 14 days, the initial dose is less or equal to 1 mg / Kg
  • Patient wo has given its written consent Patient affiliated with a social security

Exclusion Criteria:

Subjects checking one of the criteria for non-inclusion may be eligible to participate in the research. These criteria may include:

  • Early treatment of CAG disease with a dose> 1 mg / kg whatever the duration
  • Corticosteroids already started over 14 days
  • Giant arteritis cell on relapse
  • dementia syndrome
  • No compliant patient
  • Patients who live more than 150 km from the investigation center
  • Person under judicial protection, guardianship
  • Hypersensitivity to prednisone or any of its excipients
  • Infection requiring an systemic treatment
  • Evolutive viroses (Hepatitis, Herpes, varicella-zoster virus)
  • Immunization with live vaccines / mitigated during the 8 weeks preceding inclusion
  • Pregnancy, breastfeeding women or women of childbearing potential not using contraception
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Hubert De BOYSSON, MD 02 31 06 57 32 ext +33 deboysson-h@chu-caen.fr
Contact: Audrey SULTAN, PhD 02 31 06 33 58 ext +33 sultan-a@chu-caen.fr

Sponsors and Collaborators
University Hospital, Caen
University Hospital, Lille
Amiens University Hospital
University Hospital, Rouen
University Hospital, Limoges
Central Hospital Saint Quentin
Central Hospital, Valenciennes
Central Hospital, Lisieux
Investigators
Layout table for investigator information
Principal Investigator: Hubert De BOYSSON, MD University Hospital, Caen
Tracking Information
First Submitted Date  ICMJE July 5, 2019
First Posted Date  ICMJE July 9, 2019
Last Update Posted Date October 19, 2020
Estimated Study Start Date  ICMJE November 5, 2020
Estimated Primary Completion Date November 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 8, 2019) 		Patient in complete remission over a follow up of 52 weeks, without relapse [ Time Frame: Baseline up to 52 weeks ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 8, 2019)
  • First relapses rate at S28 and S52 [ Time Frame: Weeks 28 and 52 ]
  • Second relapses rate at S28 and S52 [ Time Frame: Weeks 28 and 52 ]
  • Delay between first and second relapses [ Time Frame: Baseline up to 52 weeks ]
  • Cumulative and the average dose of prednisone used [ Time Frame: Weeks 28 and 52 ]
  • Number of patient with corticosteroids dependence at week 52 [ Time Frame: Baseline up to 52 weeks ]
  • Safety according CTCAE v5.0 [ Time Frame: Baseline up to 52 weeks ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Giant Cell Arteritis: Comparison Between Two Standardized Corticosteroids Tapering
Official Title  ICMJE A Randomized, Controled, Open Label Trial: Comparison Between Two Standardized Corticosteroids Tapering, Respectively Short (North American) and Long (European), in Giant Cell Arteritis
Brief Summary

Corticosteroid therapy has always been the standard treatment for giant cell arteritis (GCA), with very good initial clinical efficacy but a high relapse rate when it declines.

The target population of this condition, often elderly, is particularly exposed to the numerous undesirable effects of corticosteroid therapy, and this especially as its duration lengthens with the re-increases of doses according to relapses: metabolic complications, osteo-muscular , infectious or neuropsychiatric.

Investigators propose to compare prospectively the results of a "conventional" corticosteroid regimen as recommended by European societies, to those of a "lighter and / or shorter" scheme, inspired by recent North American trials. , including the largest prospective global study in the field. Investigators hypothesize non-inferiority of the lightened regimen for relapse rate without relapse at S52, but with a decrease in treatment-related adverse events whose cumulative doses should be lower.

Investigators therefore plan to include prospectively over 3 years 150 patients, 75 for each of the two arms, with a newly diagnosed ACG. A randomization of the treatment arm will be performed and a predefined pattern of cortisone adapted to body weight will be given to the patient. Relapse rates, maintenance of remission, cumulative doses of cortisone and adverse effects of treatment will be analyzed at the 52nd week of the introduction of corticosteroid therapy. An interim analysis is planned at S28.
Detailed Description

Treatment of giant cell arteritis (GCA) relies on the use of glucocorticoids (GC), with a very good clinical response at treatment initiation. However, relapses at GC tapering are frequent. GCA population is elderly, frequently over 80 years, and is especially affected by GC-related side effects, that increase proportionally with treatment duration. Thus, metabolic, musculo-skeletal, infectious or neuro-psychiatric complications are frequent during prolonged GC use.

After GC introduction, gradual tapering is scheduled, provided the disease remains clinically and biologically controlled. In France, guidelines recommend tapering GC on an 18-24 months timeframe, while other countries, such as the USA, usually taper GC over a shorter period, often 6-8 months. Few comparative data exist on the relapse rates or the GC-related side effects in both settings. In this prospective multicenter study, two GC-tapering schedules are planned: patients in one arm (short treatment) will be treated for 28 weeks, while patients in the second arm will be treated for 52 weeks. Each starting dose of GC and tapering doses will be adapted to body weight. The primary endpoint is to compare the remission rate without relapse at W52 between the two groups and the secondary endpoints are: 1) cumulative GC doses at W52; 2) GC-related side effects and 3) number of relapses (minor and severe) in both arms at W52.

The results of this study might considerably modify future French clinical practice if investigators confirm that a shorter GC treatment does not significantly impact the disease course while reducing GC-related side effects.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Giant Cell Arteritis
Intervention  ICMJE Drug: Corticosteroids for Systemic Use

Corticosteroids tapering over 28 weeks:

J0 = 0,7 mg/kg S2 = 0,6 mg/kg S4 = 0,5 mg/kg S6 = 0,4 mg/kg S8 = 0,3 mg/kg S10 = 0,25 mg/kg S12 = 0,2 mg/kg S14 = 0,15 mg/kg S16 = 0,15 mg/kg S20 = 0,1 mg/kg S24 = 0,05 mg/kg S28 = 0 mg/kg

Corticosteroids tapering over 52 weeks:

J0 = 0,7 mg/kg S2 = 0,6 mg/kg S4 = 0,6 mg/kg S6 = 0,5 mg/kg S8 = 0,4 mg/kg S10 = 0,3 mg/kg S12 = 0,25 mg/kg S14 = 0,2 mg/kg S16 = 0,175 mg/kg S20 = 0,15 mg/kg S24 = 0,125 mg/kg S28 = 0,01 mg/kg S32 to S52: - 1mg per month
Study Arms  ICMJE
  • Experimental: Short tapering corticosteroids
    Corticosteroid taper over 28 weeks
    Intervention: Drug: Corticosteroids for Systemic Use
  • Active Comparator: Long tapering corticosteroids
    Corticosteroid taper over 52 weeks
    Intervention: Drug: Corticosteroids for Systemic Use
Publications *
  • Bienvenu B, Ly KH, Lambert M, Agard C, André M, Benhamou Y, Bonnotte B, de Boysson H, Espitia O, Fau G, Fauchais AL, Galateau-Sallé F, Haroche J, Héron E, Lapébie FX, Liozon E, Luong Nguyen LB, Magnant J, Manrique A, Matt M, de Menthon M, Mouthon L, Puéchal X, Pugnet G, Quemeneur T, Régent A, Saadoun D, Samson M, Sène D, Smets P, Yelnik C, Sailler L, Mahr A; Groupe d'Étude Français des Artérites des gros Vaisseaux, under the Aegis of the Filière des Maladies Auto-Immunes et Auto-Inflammatoires Rares. Management of giant cell arteritis: Recommendations of the French Study Group for Large Vessel Vasculitis (GEFA). Rev Med Interne. 2016 Mar;37(3):154-65. doi: 10.1016/j.revmed.2015.12.015. Epub 2016 Jan 29.
  • de Boysson H, Aouba A. Abatacept as Adjunctive Therapy for the Treatment of Giant Cell Arteritis: Comment on the Article by Langford et al. Arthritis Rheumatol. 2017 Jul;69(7):1504. doi: 10.1002/art.40105. Epub 2017 May 10.
  • van der Goes MC, Jacobs JW, Boers M, Andrews T, Blom-Bakkers MA, Buttgereit F, Caeyers N, Cutolo M, Da Silva JA, Guillevin L, Kirwan JR, Rovensky J, Severijns G, Webber S, Westhovens R, Bijlsma JW. Monitoring adverse events of low-dose glucocorticoid therapy: EULAR recommendations for clinical trials and daily practice. Ann Rheum Dis. 2010 Nov;69(11):1913-9. doi: 10.1136/ard.2009.124958. Epub 2010 Aug 6.
  • Proven A, Gabriel SE, Orces C, O'Fallon WM, Hunder GG. Glucocorticoid therapy in giant cell arteritis: duration and adverse outcomes. Arthritis Rheum. 2003 Oct 15;49(5):703-8.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: July 8, 2019) 		150
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 2027
Estimated Primary Completion Date November 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Age ≥ 50 years

  • Patient with temporal arteritis giant cell match 2 of the 4 criteria of the American College of Rheumatology (ACR) that given :

    • a temporal artery biopsy compatible with a diagnosis of CAG or
    • an abdominal thoracic aortitis diagnosed by Angio CT, MR angiography or PET scanner or
    • Echo Doppler compatible with a diagnosis of CAG
  • Oral corticosteroid treatment started up to 14 days, the initial dose is less or equal to 1 mg / Kg
  • Patient wo has given its written consent Patient affiliated with a social security

Exclusion Criteria:

Subjects checking one of the criteria for non-inclusion may be eligible to participate in the research. These criteria may include:

  • Early treatment of CAG disease with a dose> 1 mg / kg whatever the duration
  • Corticosteroids already started over 14 days
  • Giant arteritis cell on relapse
  • dementia syndrome
  • No compliant patient
  • Patients who live more than 150 km from the investigation center
  • Person under judicial protection, guardianship
  • Hypersensitivity to prednisone or any of its excipients
  • Infection requiring an systemic treatment
  • Evolutive viroses (Hepatitis, Herpes, varicella-zoster virus)
  • Immunization with live vaccines / mitigated during the 8 weeks preceding inclusion
  • Pregnancy, breastfeeding women or women of childbearing potential not using contraception
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 50 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Hubert De BOYSSON, MD 02 31 06 57 32 ext +33 deboysson-h@chu-caen.fr
Contact: Audrey SULTAN, PhD 02 31 06 33 58 ext +33 sultan-a@chu-caen.fr
Listed Location Countries  ICMJE Not Provided
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04012905
Other Study ID Numbers  ICMJE 17-249
2018-000344-25 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Plan Description: All individual data will be analyzed in University Hospital, Caen
Responsible Party University Hospital, Caen
Study Sponsor  ICMJE University Hospital, Caen
Collaborators  ICMJE
  • University Hospital, Lille
  • Amiens University Hospital
  • University Hospital, Rouen
  • University Hospital, Limoges
  • Central Hospital Saint Quentin
  • Central Hospital, Valenciennes
  • Central Hospital, Lisieux
Investigators  ICMJE
Principal Investigator: Hubert De BOYSSON, MD University Hospital, Caen
PRS Account University Hospital, Caen
Verification Date October 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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