In moderately to severely active rheumatoid arthritis (RA) treatment

How Quickly Can You Expect a Response?

REMICADE® – Impact too important to ignore

REMICADE®, in combination with methotrexate, is indicated for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active rheumatoid arthritis.

  • ACR Response Early RA – ASPIRE
  • ACR Response – ATTRACT

    As shown in ATTRACT

    Treatment with REMICADE® significantly improved signs and symptoms in MTX-refractory established RA, as measured after the first infusion at Week 2 through 1 year2

    Significantly more patients treated with REMICADE® 3 mg/kg + MTX q8w (n=86) achieved ACR 20 response at Week 30, compared with MTX treatment alone (n=88) (50% vs 20%, respectively; P≤0.001).

    At Week 54, treatment with REMICADE® 3 mg/kg + MTX q8w resulted in significant improvement in the signs and symptoms, as measured by the higher percentage of patients who achieved ACR 20, 50, and 70 responses vs MTX alone.2

    ACR Responses at Week 54

    At Week 2, significantly more patients treated with REMICADE® 3 mg/kg (n=171) achieved ACR 20% to <50% response vs MTX alone (n=88) (19.9% vs 4.5%; P<0.001).1

    Click here for a complete study design of ATTRACT

    SELECTED IMPORTANT SAFETY INFORMATION

    Serious and sometimes fatal side effects have been reported with REMICADE® (infliximab). Infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens (e.g., TB, histoplasmosis) have been reported. Lymphoma, including cases of fatal hepatosplenic T-cell lymphoma, and other malignancies have been reported, including in children and young adult patients. REMICADE® is contraindicated in patients with severe hypersensitivity reactions to REMICADE® and certain patients with congestive heart failure. Other serious side effects reported include melanoma and Merkel cell carcinoma, hepatitis B reactivation, hepatotoxicity, hematological events, hypersensitivity, neurological events, and lupus-like syndrome. Please see related and other Important Safety Information.

     

  • Structural Damage in RA at 54 Weeks – ASPIRE

    As shown in ASPIRE*

    Superior Inhibition of Structural Damage in Early RA1

    As shown in ASPIRE, REMICADE® in combination with methotrexate (MTX) provided superior inhibition of the progression of structural damage in moderately to severely active early RA vs MTX alone.1

    Inhibition of structural damage at 2 years in MTX-refractory established RA

    Significantly more patients treated with REMICADE® + MTX demonstrated no worsening in erosions at Week 54 (63.7%, 390/612), as measured by ≤0 change in erosion score from baseline vs MTX alone (48.7%, 110/226; P<0.001 vs MTX alone).2

    • REMICADE® + MTX not only inhibited worsening in existing erosions, but also maintained an erosion-free state in a majority of a subset of patients who were erosion-free at baseline1,2
      • Almost 8 out of 10 patients who were erosion-free at baseline maintained a score of 0 through 54 weeks of study (79% [77/98] vs 58% [23/40] with MTX alone; P=0.01)
      • Significantly more patients treated with REMICADE® + MTX had no new erosions in previously uninvolved joints (52.8% [323/612] vs 41% [93/227] with MTX alone; P=0.002)

    REMICADE® provided consistent treatment benefit in all weight groups, according to an analysis of ASPIRE1

     

    Safety data through Week 54
    Safety data through Week 54
     
      n Placebo + MTX
    Mean VW
    Score
    n REMICADE® + MTX
    Mean VW
    Score
    Diff P Value
    All Subjects 282 0.323 722 -0.126 0.449 <0.001
    Weight            
    <65 kg 71 0.382 161 -0.168 0.550 <0.001
    ≥65 kg to <80 kg 100 0.309 264 -0.117 0.427 <0.001
    ≥80 kg 109 0.271 294 -0.100 0.371 <0.001
     
     
    • Assessments of continuous variables were determined by comparing results among treatment groups by using analyses of variance of van der Waerden (VW) normal scores. Consistent treatment benefit was observed for subgroups based on body weight
    • Weight-based dosing demonstrated in a range of patients (<65 kg, ≥65 kg to <80 kg, and ≥80 kg)
    • Among patients treated with REMICADE®, vdH-S score at 1 year was maintained across a broad weight range of RA patients

    Click here for a complete study design of ASPIRE

    SELECTED IMPORTANT SAFETY INFORMATION

    Serious and sometimes fatal side effects have been reported with REMICADE® (infliximab). Infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens (e.g., TB, histoplasmosis) have been reported. Lymphoma, including cases of fatal hepatosplenic T-cell lymphoma, and other malignancies have been reported, including in children and young adult patients. REMICADE® is contraindicated in patients with severe hypersensitivity reactions to REMICADE® and certain patients with congestive heart failure. Other serious side effects reported include melanoma and Merkel cell carcinoma, hepatitis B reactivation, hepatotoxicity, hematological events, hypersensitivity, neurological events, and lupus-like syndrome. Please see related and other Important Safety Information.

     

  • Structural Damage in RA at 54 and 102 Weeks – ATTRACT

    As shown in ATTRACT

    Sustained inhibition of structural damage in RA1

    REMICADE® achieved inhibition of the progression of structural damage at Week 54 and maintained through 2 years in methotrexate (MTX)-refractory established RA.1

    Inhibition of structural damage at 2 years in MTX-refractory established RA

    • In a subset of all patients in the ATTRACT study, more patients in the combined REMICADE + MTX groups (53.7%; n=268) were free of new erosions, compared with patients treated with MTX alone (19.6%; n=51)1#

    Click here for a complete study design of ATTRACT

    SELECTED IMPORTANT SAFETY INFORMATION

    Serious and sometimes fatal side effects have been reported with REMICADE® (infliximab). Infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens (e.g., TB, histoplasmosis) have been reported. Lymphoma, including cases of fatal hepatosplenic T-cell lymphoma, and other malignancies have been reported, including in children and young adult patients. REMICADE® is contraindicated in patients with severe hypersensitivity reactions to REMICADE® and certain patients with congestive heart failure. Other serious side effects reported include melanoma and Merkel cell carcinoma, hepatitis B reactivation, hepatotoxicity, hematological events, hypersensitivity, neurological events, and lupus-like syndrome. Please see related and other Important Safety Information.

     

  • Physical Function – ASPIRE AND ATTRACT

    As shown in ASPIRE

    Greater Improvement in HAQ-DI2*

    • In ASPIRE, both REMICADE® treatment groups showed greater improvement in HAQ-DI from baseline averaged over time through Week 54 compared with MTX alone (0.7 for REMICADE® + MTX vs 0.6 for MTX alone; P≤0.001)
    • No worsening in the SF-36 mental component summary score was observed

    Click here for a complete study design of ASPIRE

    As shown in ATTRACT

    REMICADE® + MTX showed a significantly greater improvement in HAQ-DI and SF-36 physical component summary score averaged over time through 54 weeks compared with placebo + MTX2#**

    • No worsening in the SF-36 mental component summary score
    • The median (interquartile range) improvement from baseline to Week 54 in HAQ-DI was 0.1 (-0.1, 0.5) for the placebo + MTX group and 0.4 (0.1, 0.9) for REMICADE® + MTX (P<0.001)
    • Both HAQ-DI and SF-36 effects were maintained through Week 102. Approximately 80% of patients in all doses/schedules of REMICADE® + MTX remained in the trial through 102 weeks

    Click here for a complete study design of ATTRACT

    SELECTED IMPORTANT SAFETY INFORMATION

    Serious and sometimes fatal side effects have been reported with REMICADE® (infliximab). Infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens (e.g., TB, histoplasmosis) have been reported. Lymphoma, including cases of fatal hepatosplenic T-cell lymphoma, and other malignancies have been reported, including in children and young adult patients. REMICADE® is contraindicated in patients with severe hypersensitivity reactions to REMICADE® and certain patients with congestive heart failure. Other serious side effects reported include melanoma and Merkel cell carcinoma, hepatitis B reactivation, hepatotoxicity, hematological events, hypersensitivity, neurological events, and lupus-like syndrome. Please see related and other Important Safety Information.

     

  • Dosing to Clinical Response – START

    As shown in START

    Increased doses of REMICADE® were effective in patients who did not initially respond to treatment or who flared after initial response

    The primary objective was to assess the relative risk of serious infection within 22 weeks of initiating therapy with REMICADE® + MTX in subjects matching clinical practice demographics (including severity of disease, background DMARD use, and concomitant disease). Secondary objectives measured: the safety and efficacy of dose-escalation regimens in patients with an incomplete response to the initial dose of REMICADE® 3 mg/kg every 8 weeks; the safety of REMICADE®+MTX after 1 year; and the efficacy of REMICADE®+MTX in subjects with RA who reflected demographis seen in clinical practice.

    In Group 2 through Week 54, dose adjustments followed an incomplete response or flare. Response criteria: ≥20% improvement from baseline in the combined tender joint count (TJC) and swollen joint count (SJC), beginning at Week 22. Flare: ≥50% diminution in improvement in the combined TJC and SJC from baseline to the time at which response was initially achieved (at Week 22 or thereafter)

    • Two-thirds of patients required no dose adjustments (220/360)6
    • Threshold of response was achieved by 80% of patients who required dose adjustments (80/100)4‡‡III
    • Threshold of response was defined as a 20% improvement from baseline in the combined TJC and SJC, beginning at Week 22
    • More than 75% of patients who did not initially respond (primary nonresponders, 41/53) achieved response after oneor more dose increases with REMICADE®
    • 83% of patients who experienced a flare (secondary nonresponders, 39/47) achieved response after one or more dose increases with REMICADE®6¶¶

    Group 2 - Patient Response to Remicade 3mg/kg With or Without Dose Adjustments Beginning at Week 22

    Click here for a complete study design of START

    SELECTED IMPORTANT SAFETY INFORMATION

    Serious and sometimes fatal side effects have been reported with REMICADE® (infliximab). Infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens (e.g., TB, histoplasmosis) have been reported. Lymphoma, including cases of fatal hepatosplenic T-cell lymphoma, and other malignancies have been reported, including in children and young adult patients. REMICADE® is contraindicated in patients with severe hypersensitivity reactions to REMICADE® and certain patients with congestive heart failure. Other serious side effects reported include melanoma and Merkel cell carcinoma, hepatitis B reactivation, hepatotoxicity, hematological events, hypersensitivity, neurological events, and lupus-like syndrome. Please see related and other Important Safety Information.

     

*
ASPIRE (Active-controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset): a 54-week, multicenter, double-blind, active treatment-controlled, randomized, phase 3 study of REMICADE® with methotrexate (MTX) in 1004 MTX-naive patients with moderately to severely active early rheumatoid arthritis (RA) (≥3 months and ≤3 years from the date of diagnosis). The coprimary endpoints were reduction of signs and symptoms and inhibition of structural damage at Week 54, and improvement in physical function from Week 30 to Week 54. Patients were randomized into 1 of 3 treatment groups in a 5:5:4 ratio: 3 mg/kg REMICADE® + MTX (n=359), 6 mg/kg REMICADE® + MTX (n=363), and placebo + MTX (n=282). REMICADE® or placebo was infused at Weeks 0, 2, and 6, and every 8 weeks thereafter. MTX was started at 7.5 mg/week and gradually increased to 20 mg/week by Week 8. All patients were to maintain a target MTX dose of 20 mg/week for the duration of the trial, whenever possible.
 
ACR response was measured at Weeks 2, 6, 14, 30, and 54 in combination with MTX.1
 
All doses/schedules include REMICADE® 3 mg/kg every 8 weeks and REMICADE® 6 mg/kg every 8 weeks, in combination with MTX. Induction doses were administered at Weeks 0, 2, and 6 and maintenance doses were administered every 8 weeks thereafter in combination with MTX.
 
§
Visual Analog Scale (0=best, 10=worst).2
 
II
Health Assessment Questionnaire, measurement of 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities (0=best, 3=worst).2
 
ATTRACT (Anti-TNF Trial in Rheumatoid Arthritis with Concomitant Therapy): a 2-year, multicenter, double-blind, placebo-controlled, randomized, phase 3 study of REMICADE® with methotrexate (MTX) in 428 patients with moderately to severely active RA. Primary endpoints: reduction of signs and symptoms, inhibition of structural damage, and improvement in physical function. Nearly 50% of patients had advanced disease; all were on stable doses of MTX (no washout period). NSAIDs and corticosteroids (≤10 mg/day) permitted at stable doses; no other DMARDs allowed. Four REMICADE® groups: 3 mg/kg q 8 weeks (n=86), 3 mg/kg q 4 weeks (n=86), 10 mg/kg q 8 weeks (n=87), and 10 mg/kg q 4 weeks (n=81); patients randomized to MTX + placebo (n=88).
 
#
The total modified van der Heijde-Sharp (vdH-S) score (0-448) is a composite score of structural damage that measures the number and size of joint erosions and the degree of joint space narrowing (JSN) in the hands and feet.
 
**
Physical function and disability were assessed using the Health Assessment Questionnaire (HAQ-DI) and the general health-related quality of life questionnaire SF-36.
 
††
START (Safety Trial for Rheumatoid Arthritis with REMICADE® Therapy): a 54-week, randomized, multicenter, double-blind, 3-arm, parallel-group, phase 3 study of the safety of REMICADE® in combination with methotrexate (MTX) in subjects with RA. The primary objective was to assess the relative risk of serious infection within 22 weeks of initiating therapy with REMICADE® + MTX in subjects matching clinical practice demographics (including severity of disease, background DMARD use, and concomitant disease). Secondary objectives measured: the safety and efficacy of dose-escalation regimens in patients with an incomplete response to the initial dose of REMICADE® 3 mg/kg every 8 weeks; the safety of REMICADE® + MTX after 1 year; and the efficacy of REMICADE® + MTX in subjects with RA who reflected demographics seen in clinical practice. Patients (N=1084) were randomized in a 1:1:1 ratio to 1 of 3 treatment groups: placebo infusions through Week 14, followed by REMICADE® 3 mg/kg infusions every 8 weeks through Week 46 (Group 1, n=363); REMICADE® 3 mg/kg infusions every 8 weeks through Week 46, with dose escalation from Week 22 to 46 by 1.5 mg/kg increments, if the patient had an inadequate response (Group 2, n=360); and REMICADE® 10 mg/kg infusions every 8 weeks through Week 46 (Group 3, n=361).
 
‡‡
109 patients received at least 1 dose escalation; however, 9 did so in error. These patients were not included in the efficacy analysis but were included in the safety analysis.
 
§§
The median dose of MTX was 15 mg/week.
 
IIII
Primary nonresponder: >20% improvement from baseline in the combined TJC and SJC, beginning at Week 22.
 
¶¶
Secondary nonresponder: ≥50% worsening in the level response after Week 22.
 
References:
  1. Data on file. Janssen Biotech, Inc.
  2. REMICADE® (infliximab) Prescribing Information. Janssen Biotech, Inc.
  3. St. Clair EW, van der Heijde DMFM, Smolen JS, et al; for the Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset Study Group. Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial. Arthritis Rheum. 2004;50:3432-3443.
  4. Lipsky PE, van der Heijde DMFM, St. Clair EW, et al; for the Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. Infliximab and methotrexate in the treatment of rheumatoid arthritis. N Engl J Med. 2000;343:1594-1602.
  5. Maini RN, Breedveld FC, Kalden JR, et al; for the Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. Sustained improvement over two years in physical function, structural damage, and signs and symptoms among patients with rheumatoid arthritis treated with infliximab and methotrexate. Arthritis Rheum. 2004;50:1051-1065.
  6. Rahman MU, Strusberg I, Geusens P, et al. Double-blinded infliximab dose escalation in patients with rheumatoid arthritis. Ann Rheum Dis. 2007;66:1233-1238.

 

SERIOUS INFECTIONS

Patients treated with REMICADE® (infliximab) are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. Discontinue REMICADE® if a patient develops a serious infection or sepsis.

Reported infections include:

  • Active tuberculosis (TB), including reactivation of latent TB. Patients frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent TB before and during treatment with REMICADE®.1,2 Treatment for latent infection should be initiated prior to treatment with REMICADE®.
  • Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis and pneumocystosis. Patients may present with disseminated, rather than localized, disease. Empiric anti-fungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness.
  • Bacterial, viral, and other infections due to opportunistic pathogens, including Legionella and Listeria.

The risks and benefits of treatment with REMICADE® should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Closely monitor patients for the development of signs and symptoms of infection during and after treatment with REMICADE®, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy.

Risk of infection may be higher in patients greater than 65 years of age, pediatric patients, patients with co-morbid conditions and/or patients taking concomitant immunosuppressant therapy. In clinical trials, other serious infections observed in patients treated with REMICADE® included pneumonia, cellulitis, abscess, and skin ulceration.

MALIGNANCIES
Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, including REMICADE®. Approximately half of these cases were lymphomas, including Hodgkin's and non-Hodgkin's lymphoma. The other cases represented a variety of malignancies, including rare malignancies that are usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months after the first dose of therapy. Most of the patients were receiving concomitant immunosuppressants.

Postmarketing cases of hepatosplenic T-cell lymphoma, a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers, including REMICADE®. These cases have had a very aggressive disease course and have been fatal. All reported REMICADE® cases have occurred in patients with Crohn’s disease or ulcerative colitis and the majority were in adolescent and young adult males. All of these patients had received treatment with azathioprine or 6-mercaptopurine concomitantly with REMICADE® at or prior to diagnosis. Carefully assess the risks and benefits of treatment with REMICADE®, especially in these patient types.

In clinical trials of all TNF inhibitors, more cases of lymphoma were observed compared with controls and the expected rate in the general population. However, patients with Crohn’s disease, rheumatoid arthritis, or plaque psoriasis may be at higher risk for developing lymphoma. In clinical trials of some TNF inhibitors, including REMICADE®, more cases of other malignancies were observed compared with controls. The rate of these malignancies among patients treated with REMICADE® was similar to that expected in the general population whereas the rate in control patients was lower than expected. Cases of acute and chronic leukemia have been reported with postmarketing TNF-blocker use. As the potential role of TNF inhibitors in the development of malignancies is not known, caution should be exercised when considering treatment of patients with a current or a past history of malignancy or other risk factors such as chronic obstructive pulmonary disease (COPD).

Melanoma and Merkel cell carcinoma have been reported in patients treated with TNF-blocker therapy, including REMICADE®. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer.

CONTRAINDICATIONS

REMICADE® is contraindicated in patients with moderate to severe (NYHA Class III/IV) congestive heart failure (CHF) at doses greater than 5 mg/kg. Higher mortality rates at the 10 mg/kg dose and higher rates of cardiovascular events at the 5 mg/kg dose have been observed in these patients. REMICADE® should be used with caution and only after consideration of other treatment options. Patients should be monitored closely. Discontinue REMICADE® if new or worsening CHF symptoms appear. REMICADE® should not be (re)administered to patients who have experienced a severe hypersensitivity reaction or to patients with hypersensitivity to murine proteins or other components of the product.

HEPATITIS B REACTIVATION

TNF inhibitors, including REMICADE®, have been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic carriers. Some cases were fatal. Patients should be tested for HBV infection before initiating REMICADE®. For patients who test positive, consult a physician with expertise in the treatment of hepatitis B. Exercise caution when prescribing REMICADE® for patients identified as carriers of HBV and monitor closely for active HBV infection during and following termination of therapy with REMICADE®. Discontinue REMICADE® in patients who develop HBV reactivation and initiate antiviral therapy with appropriate supportive treatment. Exercise caution when considering resumption of REMICADE® and monitor patients closely.

HEPATOTOXICITY

Severe hepatic reactions, including acute liver failure, jaundice, hepatitis, and cholestasis have been reported rarely in patients receiving REMICADE® postmarketing. Some cases were fatal or required liver transplant. Aminotransferase elevations were not noted prior to discovery of liver injury in many cases. Patients with symptoms or signs of liver dysfunction should be evaluated for evidence of liver injury. If jaundice and/or marked liver enzyme elevations (eg, ≥5 times the upper limit of normal) develop, REMICADE® should be discontinued, and a thorough investigation of the abnormality should be undertaken.

HEMATOLOGIC EVENTS

Cases of leukopenia, neutropenia, thrombocytopenia, and pancytopenia (some fatal) have been reported. The causal relationship to REMICADE® therapy remains unclear. Exercise caution in patients who have ongoing or a history of significant hematologic abnormalities. Advise patients to seek immediate medical attention if they develop signs and symptoms of blood dyscrasias or infection. Consider discontinuation of REMICADE® in patients who develop significant hematologic abnormalities.

HYPERSENSITIVITY

REMICADE® has been associated with hypersensitivity reactions that differ in their time of onset. Acute urticaria, dyspnea, and hypotension have occurred in association with infusions of REMICADE®. Serious infusion reactions including anaphylaxis were infrequent. Medications for the treatment of hypersensitivity reactions should be available.

NEUROLOGIC EVENTS

TNF inhibitors, including REMICADE®, have been associated in rare cases with CNS manifestation of systemic vasculitis, seizure, and new onset or exacerbation of CNS demyelinating disorders, including multiple sclerosis and optic neuritis, and peripheral demyelinating disorders, including Guillain-Barré syndrome. Exercise caution when considering REMICADE® in patients with these disorders and consider discontinuation if these disorders develop.

AUTOIMMUNITY

Treatment with REMICADE® may result in the formation of autoantibodies and, rarely, in development of a lupus-like syndrome. Discontinue treatment if symptoms of a lupus-like syndrome develop.

ADVERSE REACTIONS

In clinical trials, the most common REMICADE® adverse reactions occurring in >10% of patients included infections (eg, upper respiratory, sinusitis, and pharyngitis), infusion-related reactions, headache, and abdominal pain.

USE WITH OTHER DRUGS

Concomitant use of REMICADE® with anakinra, abatacept, tocilizumab, or other biologics used to treat the same conditions as REMICADE® is not recommended because of the possibility of an increased risk of infection. Care should be taken when switching from one biologic to another, since overlapping biological activity may further increase the risk of infection.

LIVE VACCINES/THERAPEUTIC INFECTIOUS AGENTS

Live vaccines or therapeutic infectious agents should not be given with REMICADE® due to the possibility of clinical infections, including disseminated infections.

Bring pediatric patients up to date with all vaccinations prior to initiating REMICADE®. Exercise caution in the administration of live vaccines to infants born to female patients treated with REMICADE® during pregnancy.

For more information, please see full Prescribing Information and Medication Guide for REMICADE®.
Provide the Medication Guide to your patients and encourage discussion.

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References:
  1. 1.American Thoracic Society, Centers for Disease Control and Prevention. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med. 2000;161:S221-S247.
    2. See latest Centers for Disease Control guidelines and recommendations for tuberculosis testing in immunocompromised patients.



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