Treatment With Leflunomide in Patients With Polymyalgia Rheumatica (PMRLEFRCT)

A Multicenter Randomized Placebo Controlled Treatment Study of Leflunomide in Polymyalgia Rheumatica

Over the last decades outcome has greatly improved for rheumatoid arthritis (RA) and spondyloarthritis (SpA). This is in sharp contrast to the situation for polymyalgia rheumatica (PMR), with a lifetime prevalence of 2.4% for women and 1.7% for men, PMR is the commonest auto-inflammatory musculoskeletal disease in adults aged ≥50 years. Due to population ageing, the number of PMR patients will likely double in the decades to come (CBS). Glucocorticoids (GC) are the mainstay of treatment. However, there is an unmet medical need of alternatives in the treatment of PMR as 50% of patients will relapse or have difficulties to reduce the corticosteroid doses. Also, there is increasing awareness of steroid related toxicity and in addition, long-term toxicity is a well-known side-effect of glucocorticoids in PMR.

Low dose methotrexate (< 10 mg per week) has been tested in two blinded randomized control trials and 4 open label studies and has shown low to moderate efficacy as corticosteroid-sparing agent. Studies on tumor necrosis factor (TNF) blockers yielded negative results. The effectiveness of leflunomide has only been convincingly demonstrated in case series.

The high rate of relapses and adverse events in steroid treated patients indicate that alternative adjuvant agents are needed.

There is evidence that leflunomide could serve as steroid sparing agent and that leflunomide can be used to prevent relapses in the clinical management of polymyalgia rheumatica.

We will perform a randomized placebo controlled trial. Eligible patients will be randomly assigned in a 1:1 ratio receiving either leflunomide 20 mg once daily + glucocorticoids , or placebo + glucocorticoids.

Study Overview

• Status: Unknown
• Conditions: Polymyalgia Rheumatica
• Intervention / Treatment: Drug: Leflunomide 20 mg; Drug: Prednisolone

Detailed Description

Over the last decades outcome has greatly improved for rheumatoid arthritis (RA) and spondyloarthritis (SpA). This is in sharp contrast to the situation for polymyalgia rheumatica (PMR), with a lifetime prevalence of 2.4% for women and 1.7% for men, PMR is the commonest auto-inflammatory musculoskeletal disease in adults aged ≥50 years. Due to population ageing, the number of PMR patients will likely double in the decades to come (CBS). Glucocorticoids (GC) are the mainstay of treatment. However, there is an unmet medical need of alternatives in the treatment of PMR as 50% of patients will relapse or have difficulties to reduce the corticosteroid doses. Also, there is increasing awareness of steroid related toxicity and in addition, long-term toxicity is a well-known side-effect of glucocorticoids in PMR.

Low dose methotrexate (< 10 mg per week) has been tested in two blinded randomized control trials and 4 open label studies and has shown low to moderate efficacy as corticosteroid-sparing agent. Studies on TNF blockers yielded negative results. The effectiveness of leflunomide has only been convincingly demonstrated in case series.

The high rate of relapses and adverse events in steroid treated patients indicate that alternative adjuvant agents are needed.

There is evidence that leflunomide could serve as steroid sparing agent and that leflunomide can be used to prevent relapses in the clinical management of polymyalgia rheumatica.

We will perform a randomized placebo controlled trial. Eligible patients will be randomly assigned in a 1:1 ratio receiving either leflunomide 20 mg once daily + glucocorticoids , or placebo + glucocorticoids.

Primary endpoint The clinically relevant lower total number of relapses in leflunomide treated PMR patients as compared to placebo treated patients at 18 months.

Secondary endpoints

1. Steroid sparing capacity of leflunomide in patients with newly diagnosed PMR. Glucocorticoid sparing is expressed as a reduction of the cumulative glucocorticoid dose in the first 2 years of treatment.
2. Less time needed to reach both remission on glucocorticoids and glucocorticoid free remission
3. Less GC side effects in leflunomide PMR patient group

The first 2 weeks patients will receive leflunomide 20 mg every other day in order to prevent early drug withdrawal due to side effects. After 2 weeks leflunomide will be increased to 20 mg per day.

In case leflunomide has to be stopped due to side effects or inefficacy methotrexate will be used as rescue therapy 10 mg per week open label, based on the evidence that 10 mg methotrexate per week is steroid sparing. Those patients will be classified as non-responder.

Randomization will be stratified by age, gender and weight. Therefore, blocked randomization with variable block size will be performed.

Patients in both groups will be started on prednisolone 15 mg once daily and will be randomized within 2 weeks of the start of steroid therapy. The steroids will be tapered according to a short fixed protocol starting with 15 mg a day with a slow gradual taper till 0 in week 27.

Criteria for relapse or recurrence of PMR Relapse or recurrence will be measured according to an adaptation, based on expert opinion, to consensus criteria for PMR.

Relapse / recurrence Patient global higher than 3/ 10 and Physician global higher than 1/10 and An increased C reactive protein (CRP) ( > 5 mg/L) Is called a relapse if it was observed during steroid tapering, and is called a Recurrence if it was observed after steroid withdrawal.

Criteria for remission Patient global 3/ 10 or less and Physician global 1/10 or less and A normal CRP ( < 5 mg/L)

Secondary outcome measure PMR-AS The PMR-AS (Leeb and Bird) is a composite score with the following items: Physician global, Pt global, CRP, ability to raise the shoulders on examination, and duration of morning stiffness in minutes.

This randomized controlled trial (RCT) will assess:

1. Time to relapse and steroid-sparing capacity of leflunomide
2. PMR disease activity including patient reported outcome
3. Treatment related complications of steroids
4. Safety and tolerability of leflunomide

This blinded RCT in PMR is a unique study involving 5 centres in 4 different countries. It is the first study to use the recently developed consensus and outcome criteria in PMR which were developed by multidisciplinary groups including patients input. It is both timely and needed to fund a study in PMR since due to ageing in especially Western Europe the expectancy is that the incidence and prevalence of PMR will increase in the coming years. In brief: It is time to take PMR seriously and treat the patients with steroid sparing agents in order to prevent co-morbidities like diabetes, hypertension and osteoporosis in an ageing population.

The 5 centres (Department of Rheumatology and Immunology, Medical University Graz, Department of Rheumatology, Hospital of Southern Norway Trust Kristiansand, Kristiansand, Norway, The Department of Rheumatology, Southend University Hospital, Westcliff-on-sea, Chapel Allerton Hospital and St James's University Hospital Leeds and the University Medical Centre Groningen) participating in this study also set up an immediate early access outpatient clinic for PMR patients.

We will keep close contact with patients and their organizations to check whether our aims are in line with their expectations.

The relevance and gain for patients will be a different approach to PMR on the level of

• Early recognition/ making an appropriate diagnosis
• Starting steroid sparing treatment in an adequate dose at baseline
• Better outcome and earlier control of PMR with less relapses and cumulative dosis of steroids (benefit of thight control).

Our study can provide substantial benefit to the society. We seek to demonstrate that relatively cheap drug like leflunomide can improve the treatment of these PMR patients and limit the occurrence of relapses and GC-related side effects. Since leflunomide is an old and cheap drug the pharmaceutical companies are not interested in funding, we hope therefore that the Dutch Arthritis Association will fund our study.

• Study Type: Interventional
• Enrollment (Anticipated): 94
• Phase: Phase 3

Contacts and Locations

Study Locations

• Netherlands
  • Almelo, Netherlands, 7609 PP
    • Recruiting
    • ZGT Almelo
    • Contact: Edgar Colin, MDPhD
    • Contact: Celina Alves, MDPhD
  • Groningen, Netherlands, 9713 GZ
    • Recruiting
    • University Medical Center Groningen
    • Contact: Elisabeth Brouwer, dr; Phone Number: +3150 3613432; Email: e.brouwer@umcg.nl
    • Contact: Maria Sandovici, dr; Phone Number: +3150 3613432; Email: m.sandovici01@umcg.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Signed written informed consent
2. Female or male aged ≥ 50 years
3. PMR according to the American College of Rheumatology (ACR)/European league Against Rheumatism (EULAR) 2012 PMR core (essential) classification criteria
4. Newly diagnosed PMR being on glucocorticoids for less than 4 weeks

Exclusion Criteria:

1. Presence of any other connective tissue disease, including vasculitis/giant-cell arteritis
2. PMR on glucocorticoids for >4 week or >25 mg/day
3. History of alcohol or drug abuse or current alcohol or drug abuse
4. Transplanted organ (except corneal transplant performed more than 3 months prior to screening)
5. Evidence (as assessed by the investigator) of active infection, presence of hepatitis B surface antigen or hepatitis C antibody in blood, HIV positivity.
6. Malignancy within 5 years prior to screening, except for non-melanoma skin cancer
7. Exposure to DMARD/biological in the last 5 years
8. Pain syndromes, e.g. fibromyalgia, drug-induced myalgia
9. Active thyroid disease
10. Neurological diseases, e.g. Parkinson's disease
11. Contraindications for Leflunomide (serious immunodeficiency, e.g. AIDS, cytopenia as defined under 12, moderate to severe kidney failure (as defined under 12), liver test abnormality (as defined under 12)

12. Laboratory abnormalities:

    • Glomerular filtration rate <50 ml/min
    • Alanine-aminotransferase (ALT) or aspartate aminotransferase (AST) >1.5x upper limit of normal
    • Platelet count <100 x 109/L (100,000/mm3)
    • Hemoglobin <85 g/L (8.5 g/dL; 5.3 mmol/L)
    • White blood cells <3.0 x 109/L (3,000/mm3)Absolute neutrophil count <2.0 x 109/L (2,000/mm3)
    • Absolute lymphocyte count <0.5 x 109/L (500/mm3)
13. Uncontrolled or poorly controlled hypertension
14. Major surgery or hospitalization within 3 month prior to screening
15. Any medical condition that could interfere with the implementation or interpretation of the study or with the safety of the patient during the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Leflunomide treatment; Patients will receive prednisolone 15 mg once daily and will be randomized within 4 weeks of the start of glucocorticoid therapy (prednisolone). Prednisolon will be tapered according to a short fixed protocol with a slow gradual taper till 0 in week 27. During the first 2 weeks after randomization patients will receive Leflunomide 20 mg every other day in order to prevent early drug withdrawal due to side effects. After 2 weeks Leflunomide will be increased to 20 mg once daily and this therapy will be continued during 12 months.	Drug: Leflunomide 20 mg; During the first 2 weeks after randomization patients will receive Leflunomide 20 mg every other day. After 2 weeks Leflunomide will be increased to 20 mg once daily and this therapy will be continued during 12 months.; Drug: Prednisolone; Patients in both groups will receive prednisolone 15 mg once daily and will be randomized within 4 weeks of the start of glucocorticoid therapy (prednisolone). Prednisolon will be tapered according to a short fixed protocol with a slow gradual taper till 0 in week 27.
Placebo Comparator: Placebo control; Patients will receive prednisolone 15 mg once daily and will be randomized within 4 weeks of the start of glucocorticoid therapy (prednisolone). Prednisolon will be tapered according to a short fixed protocol with a slow gradual taper till 0 in week 27. During the first 2 weeks after randomization patients will receive placebo 20 mg every other day in order to prevent early drug withdrawal due to side effects. After 2 weeks placebo will be increased to 20 mg once daily and this therapy will be continued during 12 months.	Drug: Prednisolone; Patients in both groups will receive prednisolone 15 mg once daily and will be randomized within 4 weeks of the start of glucocorticoid therapy (prednisolone). Prednisolon will be tapered according to a short fixed protocol with a slow gradual taper till 0 in week 27.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PMR relapse	Relapse or recurrence will be measured according to an adaptation, based on expert opinion, to consensus criteria for PMR: Patient global higher than 3/10 and; Physician global higher than 1/10 and; An increased CRP ( > 5 mg/L) It is called a "relapse" if it was observed during glucocorticoid tapering and is called a "recurrence" if it was observed after glucocorticoid withdrawal.	Within first 12 months of the study participation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time till first relapse within first 24 months	Time measured in days	Within first 24 months of the study participation
Percentage of patients with at least 1 relapse in the first 12 or 24 months	Percentage: patients with relapse in the first 12 or 24 months divided by total participating patients.	Within first 24 months of the study participation
Number of relapsing patients within the first 24 months.		Within first 24 months of the study participation
Time till glucocorticoid free remission	Total days until patient has no glucocorticoid treatment and no signs of PMR.	Within first 24 months of the study participation
Glucocorticoid-sparing effect	Glucocorticoid dose after 6, 12, 18 and 24 months.; Cumulative glucocorticoid dose after 12, 18 and 24 months	Within first 24 months of the study participation
Number of participants with adverse events and serious adverse events as assessed by MedDRA V21.0		Within first 24 months of the study participation

Collaborators and Investigators

• Sponsor: Elisabeth Brouwer
• Collaborators: Dutch Arthritis Foundation Reuma Nederland
• Investigators: Principal Investigator: Elisabeth Brouwer, University Medical Center Groningen; Principal Investigator: E.M. Colin, ZGT Almelo

Publications and helpful links

General Publications

• Dasgupta B, Borg FA, Hassan N, Alexander L, Barraclough K, Bourke B, Fulcher J, Hollywood J, Hutchings A, James P, Kyle V, Nott J, Power M, Samanta A; BSR and BHPR Standards, Guidelines and Audit Working Group. BSR and BHPR guidelines for the management of giant cell arteritis. Rheumatology (Oxford). 2010 Aug;49(8):1594-7. doi: 10.1093/rheumatology/keq039a. Epub 2010 Apr 5. No abstract available.
• Hernandez-Rodriguez J, Cid MC, Lopez-Soto A, Espigol-Frigole G, Bosch X. Treatment of polymyalgia rheumatica: a systematic review. Arch Intern Med. 2009 Nov 9;169(20):1839-50. doi: 10.1001/archinternmed.2009.352.
• van der Veen MJ, Dinant HJ, van Booma-Frankfort C, van Albada-Kuipers GA, Bijlsma JW. Can methotrexate be used as a steroid sparing agent in the treatment of polymyalgia rheumatica and giant cell arteritis? Ann Rheum Dis. 1996 Apr;55(4):218-23. doi: 10.1136/ard.55.4.218. Erratum In: Ann Rheum Dis 1996 Aug;55(8):563.
• Wagener P. [Methotrexate therapy of polymyalgia rheumatica]. Z Rheumatol. 1995 Nov-Dec;54(6):413-6. German.
• Ferraccioli G, Salaffi F, De Vita S, Casatta L, Bartoli E. Methotrexate in polymyalgia rheumatica: preliminary results of an open, randomized study. J Rheumatol. 1996 Apr;23(4):624-8.
• Feinberg HL, Sherman JD, Schrepferman CG, Dietzen CJ, Feinberg GD. The use of methotrexate in polymyalgia rheumatica. J Rheumatol. 1996 Sep;23(9):1550-2.
• Caporali R, Cimmino MA, Ferraccioli G, Gerli R, Klersy C, Salvarani C, Montecucco C; Systemic Vasculitis Study Group of the Italian Society for Rheumatology. Prednisone plus methotrexate for polymyalgia rheumatica: a randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2004 Oct 5;141(7):493-500. doi: 10.7326/0003-4819-141-7-200410050-00005.
• Cimmino MA, Salvarani C, Macchioni P, Gerli R, Bartoloni Bocci E, Montecucco C, Caporali R; Systemic Vasculitis Study Group of the Italian Society for Rheumatology. Long-term follow-up of polymyalgia rheumatica patients treated with methotrexate and steroids. Clin Exp Rheumatol. 2008 May-Jun;26(3):395-400.
• Catanoso MG, Macchioni P, Boiardi L, Pipitone N, Salvarani C. Treatment of refractory polymyalgia rheumatica with etanercept: an open pilot study. Arthritis Rheum. 2007 Dec 15;57(8):1514-9. doi: 10.1002/art.23095.
• Salvarani C, Macchioni P, Manzini C, Paolazzi G, Trotta A, Manganelli P, Cimmino M, Gerli R, Catanoso MG, Boiardi L, Cantini F, Klersy C, Hunder GG. Infliximab plus prednisone or placebo plus prednisone for the initial treatment of polymyalgia rheumatica: a randomized trial. Ann Intern Med. 2007 May 1;146(9):631-9. doi: 10.7326/0003-4819-146-9-200705010-00005.
• Kreiner F, Galbo H. Effect of etanercept in polymyalgia rheumatica: a randomized controlled trial. Arthritis Res Ther. 2010;12(5):R176. doi: 10.1186/ar3140. Epub 2010 Sep 20.
• Lally L, Forbess L, Hatzis C, Spiera R. Brief Report: A Prospective Open-Label Phase IIa Trial of Tocilizumab in the Treatment of Polymyalgia Rheumatica. Arthritis Rheumatol. 2016 Oct;68(10):2550-4. doi: 10.1002/art.39740.
• Devauchelle-Pensec V, Berthelot JM, Cornec D, Renaudineau Y, Marhadour T, Jousse-Joulin S, Querellou S, Garrigues F, De Bandt M, Gouillou M, Saraux A. Efficacy of first-line tocilizumab therapy in early polymyalgia rheumatica: a prospective longitudinal study. Ann Rheum Dis. 2016 Aug;75(8):1506-10. doi: 10.1136/annrheumdis-2015-208742. Epub 2016 Feb 29.
• Adizie T, Christidis D, Dharmapaliah C, Borg F, Dasgupta B. Efficacy and tolerability of leflunomide in difficult-to-treat polymyalgia rheumatica and giant cell arteritis: a case series. Int J Clin Pract. 2012 Sep;66(9):906-9. doi: 10.1111/j.1742-1241.2012.02981.x.
• Diamantopoulos AP, Hetland H, Myklebust G. Leflunomide as a corticosteroid-sparing agent in giant cell arteritis and polymyalgia rheumatica: a case series. Biomed Res Int. 2013;2013:120638. doi: 10.1155/2013/120638. Epub 2013 Sep 11.
• Dasgupta B, Cimmino MA, Kremers HM, Schmidt WA, Schirmer M, Salvarani C, Bachta A, Dejaco C, Duftner C, Jensen HS, Duhaut P, Poor G, Kaposi NP, Mandl P, Balint PV, Schmidt Z, Iagnocco A, Nannini C, Cantini F, Macchioni P, Pipitone N, Del Amo M, Espigol-Frigole G, Cid MC, Martinez-Taboada VM, Nordborg E, Direskeneli H, Aydin SZ, Ahmed K, Hazleman B, Silverman B, Pease C, Wakefield RJ, Luqmani R, Abril A, Michet CJ, Marcus R, Gonter NJ, Maz M, Carter RE, Crowson CS, Matteson EL. 2012 Provisional classification criteria for polymyalgia rheumatica: a European League Against Rheumatism/American College of Rheumatology collaborative initiative. Arthritis Rheum. 2012 Apr;64(4):943-54. doi: 10.1002/art.34356.
• Gran JT, Myklebust G. The incidence of polymyalgia rheumatica and temporal arteritis in the county of Aust Agder, south Norway: a prospective study 1987-94. J Rheumatol. 1997 Sep;24(9):1739-43.
• Kermani TA, Warrington KJ. Polymyalgia rheumatica. Lancet. 2013 Jan 5;381(9860):63-72. doi: 10.1016/S0140-6736(12)60680-1. Epub 2012 Oct 8. Erratum In: Lancet. 2013 Jan 5;381(9860):28.
• Matteson EL, Maradit-Kremers H, Cimmino MA, Schmidt WA, Schirmer M, Salvarani C, Bachta A, Dejaco C, Duftner C, Slott Jensen H, Poor G, Kaposi NP, Mandl P, Balint PV, Schmidt Z, Iagnocco A, Cantini F, Nannini C, Macchioni P, Pipitone N, Del Amo M, Espigol-Frigole G, Cid MC, Martinez-Taboada VM, Nordborg E, Direskeneli H, Aydin SZ, Ahmed K, Hazelman B, Pease C, Wakefield RJ, Luqmani R, Abril A, Marcus R, Gonter NJ, Maz M, Crowson CS, Dasgupta B. Patient-reported outcomes in polymyalgia rheumatica. J Rheumatol. 2012 Apr;39(4):795-803. doi: 10.3899/jrheum.110977. Epub 2012 Mar 15.
• Dasgupta B, Borg FA, Hassan N, Barraclough K, Bourke B, Fulcher J, Hollywood J, Hutchings A, Kyle V, Nott J, Power M, Samanta A; BSR and BHPR Standards, Guidelines and Audit Working Group. BSR and BHPR guidelines for the management of polymyalgia rheumatica. Rheumatology (Oxford). 2010 Jan;49(1):186-90. doi: 10.1093/rheumatology/kep303a. Epub 2009 Nov 12. No abstract available.
• Dejaco C, Singh YP, Perel P, Hutchings A, Camellino D, Mackie S, Abril A, Bachta A, Balint P, Barraclough K, Bianconi L, Buttgereit F, Carsons S, Ching D, Cid M, Cimmino M, Diamantopoulos A, Docken W, Duftner C, Fashanu B, Gilbert K, Hildreth P, Hollywood J, Jayne D, Lima M, Maharaj A, Mallen C, Martinez-Taboada V, Maz M, Merry S, Miller J, Mori S, Neill L, Nordborg E, Nott J, Padbury H, Pease C, Salvarani C, Schirmer M, Schmidt W, Spiera R, Tronnier D, Wagner A, Whitlock M, Matteson EL, Dasgupta B; European League Against Rheumatism; American College of Rheumatology. 2015 recommendations for the management of polymyalgia rheumatica: a European League Against Rheumatism/American College of Rheumatology collaborative initiative. Arthritis Rheumatol. 2015 Oct;67(10):2569-80. doi: 10.1002/art.39333.
• Metzler C, Fink C, Lamprecht P, Gross WL, Reinhold-Keller E. Maintenance of remission with leflunomide in Wegener's granulomatosis. Rheumatology (Oxford). 2004 Mar;43(3):315-20. doi: 10.1093/rheumatology/keh009. Epub 2004 Jan 6.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2019
• Primary Completion (Anticipated): November 1, 2022
• Study Completion (Anticipated): November 1, 2022

Study Registration Dates

• First Submitted: April 17, 2018
• First Submitted That Met QC Criteria: July 2, 2018
• First Posted (Actual): July 3, 2018

Study Record Updates

• Last Update Posted (Actual): June 3, 2019
• Last Update Submitted That Met QC Criteria: May 30, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Keywords: Leflunomide; PMR RCT
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Skin Diseases; Immune System Diseases; Autoimmune Diseases of the Nervous System; Autoimmune Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Muscular Diseases; Vasculitis; Skin Diseases, Vascular; Vasculitis, Central Nervous System; Arteritis; Polymyalgia Rheumatica; Giant Cell Arteritis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Anti-Inflammatory Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Prednisolone; Leflunomide
• Other Study ID Numbers: ABR57022

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Manuscript after publication
• IPD Sharing Time Frame: Within 2 years after study termination, study data will be available and published
• IPD Sharing Access Criteria: Study data will be available upon request to the principal investigator
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Clinical Study Report (CSR)

Drug and device information, study documents

• 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