A multicenter, randomized, open-label, blinded-assessor, phase 4 study in patients with early rheumatoid arthritis to compare active conventional therapy versus three biologic treatments, and two de-escalation strategies in patients who respond to treatment.

Status Authorised, recruitment pending · 4 EU/EEA countries · 25 sites · Protocol NORD-STAR

Overview

Sponsor-declared trial summary

Phase Therapeutic use (Phase IV)

Status Authorised, recruitment pending

Participants planned 705

Countries 4

Sites 25

Rheumatoid Arthritis

The global aim of this study is to assess and compare 1) the proportion of subjects who achieve remission with active conventional therapy (ACT) versus three different biologic therapies; and 2) two alternative de-escalation strategies in patients who respond to first-line therapy.

Key facts

Sponsor: Karolinska Institutet
Participant type: Patients
Age range: 18-64 years, 65+ years
Gender: Male and Female
Therapeutic area: Diseases [C] - Musculoskeletal Diseases [C05]
Decision date (initial): 2024-11-12
Transition trial: Yes
Low-intervention: No
Rare-disease indication: No
Vulnerable population: No

External identifiers

EU CT number: 2024-516723-14-00
EudraCT number: 2011-004720-35
ClinicalTrials.gov: NCT01491815

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

Conditions and MedDRA coding

Rheumatoid Arthritis

Version	Level	Code	Term	System organ class
23.1	PT	10039073	Rheumatoid arthritis	100000004859

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

Subject is ≥18 years of age.
Subject has a diagnosis of RA as defined by the newly established ACR/EULAR criteria, 2010.
<24 months from arthritis symptom debut (symptom duration will be registered).
Subject must have DAS28 (CRP) > 3.2.
≥ 2 swollen joints AND ≥ 2 tender joints (based on 66/68 joint count)
Subject must fulfill one of the following three criteria: RF positive OR ACPA positive OR CRP ≥10 mg/L.
Female subject is either not of childbearing potential (postmenopausal, surgically sterile etc.), or is of childbearing potential and practicing one of the following methods of birth control throughout the study and for 150 days after study completion: • Intrauterine device (IUD) • Contraceptives (oral, parenteral, patch) for three months prior to study drug administration) • A vasectomized partner
Female subjects of childbearing potential must have a negative pregnancy test at the Screening visit.
Subject is judged to be in good general health as determined by the principal investigator based upon the results of medical history, laboratory profile, physical examination, chest X-ray (CXR), and 12-lead electrocardiogram (ECG) performed at Screening.
Subjects must be able and willing to provide written informed consent and comply with the requirements of this study protocol.
Subjects must be able and willing to self-administer s.c. injections or have a qualified person available to administer s.c. injections.

Exclusion criteria 23

Subject has been previously treated with disease modifying antirheumatic drugs (DMARDs) for rheumatic diseases
Current active inflammatory joint disease other than RA.
Subject has had a dose of prednisone (or equivalent) >7.5 mg/day or has had a dose change within the preceding 4 weeks.
Subject has been treated with intra-articular or parenteral administration of corticosteroids in the preceding 4 weeks. Inhaled corticosteroids for stable medical conditions are allowed.
Subject has undergone joint surgery within the preceding two months (at joints to be assessed within the study).
Subject has chronic arthritis diagnosed before age 17 years.
Subject has a history of an allergic reaction or significant sensitivity to constituents of study drugs.
Subject has been treated with any investigational drug within one month prior to screening visit.
Active infection of any kind (excluding fungal infections of nail beds), or any major episode of infection requiring hospitalization within 4 weeks of screening.
Subject has a poorly controlled medical condition, such as uncontrolled diabetes, unstable heart disease, congestive heart failure, recent cerebrovascular accidents and any other condition which, in the opinion of the investigator, would put the subject at risk by participation in the study.
Subject has a history of clinically significant hematologic (e.g., severe anemia, leukopenia, thrombocytopenia), renal or liver disease (e.g., fibrosis, cirrhosis, hepatitis).
Subject has history of neurologic symptoms suggestive of central nervous system (CNS) demyelinating disease and/or diagnosis of central demyelinating disease.
Subject has history of cancer or lymphoproliferative disease. Allowable exceptions: a. Successfully treated cutaneous squamous cell or basal cell carcinoma b. Localized carcinoma in situ of the cervix c. Curatively treated malignancy (treatment terminated) > 5 years prior to screening
Subject has a history of listeriosis, histoplasmosis, untreated TB, persistent chronic infections, or recent active infections requiring hospitalization or treatment with intravenous (iv) anti-infectives within 30 days or oral anti-infectives within 14 days prior to the BL visit.
Subjects will be evaluated for latent TB infection with a PPD or QuantiFERON test and X-ray. Subjects with evidence for latent TB will not be enrolled but first assessed according to local guidelines.
Subject is known to have immune deficiency, history of Human Immunodeficiency Virus (HIV) or is otherwise severely immunocompromised.
Female subject who is pregnant or breast-feeding or considering becoming pregnant during the study or within 150 days after the last dose of study medication.
Men who are planning to father a child during the time they are included in the study.
Subject has a history of clinically significant drug or alcohol usage in the last year.
Subject has a chronic widespread pain syndrome.
Subject is considered by the investigator, for any reason, to be an unsuitable candidate for the study
Subject is unwilling to comply with the study protocol.
Screening clinical laboratory analyses show any of the following abnormal laboratory results: a. Aspartate transaminase (AST) or alanine transaminase (ALT) > 1.75 times upper limit of normal (ULN). b. Positive serum human chorionic gonadotropin (hCG). c. Positive tests for hepatitis B surface antigen (HBsAg) or hepatitis C serology indicative of current infection. d. Creatinine levels > 2x the ULN. If creatinine 1-2 times ULN, check GFR. e. Hemoglobin < 90 g/L. f. Absolute neutrophil count (ANC) < 1.5 x 10^3/uL. g. Serum total bilirubin ≥ 1.5 mg/dL (≥26 micromol/L).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

Treatment Part 1: The primary efficacy outcome is the proportion of patients in remission at week 24 from baseline according to CDAI. Treatment Part 1: The primary radiographic outcome is the progression of total Sharp van der Heijde score after 48 weeks from baseline. Treatment Part 2: The primary efficacy outcome is the proportion of patients in remission according to CDAI, at the time point 24 weeks after the dose was first reduced.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Cimzia 200 mg solution for injection in pre-filled syringe

PRD326002 · Product

Active substance: Certolizumab Pegol
Pharmaceutical form: SOLUTION FOR INJECTION
Route of administration: SUBCUTANEOUS INJECTION
Max daily dose: 14.29 mg milligram(s)
Max total dose: 62400 mg milligram(s)
Max treatment duration: 625 Week(s)
Authorisation status: Authorised
ATC code: L04AB05 — -
Marketing authorisation: EU/1/09/544/002
MA holder: UCB PHARMA S.A. (ANDERL BE)
MA country: EU
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

RoActemra 162 mg solution for injection in pre-filled syringe.

PRD1576593 · Product

Active substance: Tocilizumab
Pharmaceutical form: SOLUTION FOR INJECTION
Route of administration: SUBCUTANEOUS INJECTION
Max daily dose: 23.14 mg milligram(s)
Max total dose: 101250 mg milligram(s)
Max treatment duration: 625 Week(s)
Authorisation status: Authorised
ATC code: L04AC07 — -
Marketing authorisation: EU/1/08/492/007
MA holder: ROCHE REGISTRATION GMBH
MA country: EU
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

RoActemra 20 mg/mL concentrate for solution for infusion

PRD2159900 · Product

Active substance: Tocilizumab
Pharmaceutical form: SOLUTION FOR INFUSION
Route of administration: INFUSION
Max daily dose: 0.29 mg/kg milligram(s)/kilogram
Max total dose: 1248 mg/kg milligram(s)/kilogram
Max treatment duration: 625 Week(s)
Authorisation status: Authorised
ATC code: L04AC07 — -
Marketing authorisation: EU/1/08/492/006
MA holder: ROCHE REGISTRATION GMBH
MA country: Liechtenstein
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Abatacept

SCP149772 · ATC

Active substance: Abatacept
Route of administration: SUBCUTANEOUS INJECTION
Max daily dose: 17.86 mg milligram(s)
Max total dose: 78125 mg milligram(s)
Max treatment duration: 625 Week(s)
Authorisation status: Authorised
ATC code: L04AA24 — ABATACEPT
Marketing authorisation: -
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Comparator 4

Betamethasone Sodium Phosphate

SCP107974752 · ATC

Active substance: Betamethasone Sodium Phosphate
Substance synonyms: BETAMETHASONE DISODIUM PHOSPHATE
Route of administration: ORAL
Max daily dose: 20 mg milligram(s)
Max total dose: 1820 mg milligram(s)
Max treatment duration: 36 Week(s)
Authorisation status: Authorised
ATC code: H02AB06 — PREDNISOLONE
Marketing authorisation: -
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Triamcinolone Hexacetonide 20 mg/ml suspension for injection

PRD1577772 · Product

Active substance: Triamcinolone Hexacetonide
Pharmaceutical form: SUSPENSION FOR INJECTION
Route of administration: INTRA-ARTICULAR INJECTION
Max daily dose: 4 ml millilitre(s)
Max total dose: 84 ml millilitre(s)
Max treatment duration: 160 Week(s)
Authorisation status: Authorised
ATC code: H02AB08 — TRIAMCINOLONE
Marketing authorisation: PL17509/0061
MA holder: ESTEVE PHARMACEUTICALS LTD
MA country: XI
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Sulfasalazine

SCP130065 · ATC

Active substance: Sulfasalazine
Substance synonyms: SULPHASALAZINE, SALICYLAZOSULFAPYRIDINE, SASP
Route of administration: ORAL
Max daily dose: 2 g gram(s)
Max total dose: 8750 g gram(s)
Max treatment duration: 625 Week(s)
Authorisation status: Authorised
ATC code: A07EC01 — SULFASALAZINE
Marketing authorisation: -
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Hydroxychloroquine Sulfate

SCP134762 · ATC

Active substance: Hydroxychloroquine Sulfate
Substance synonyms: 2-[4-[(7-CHLOROQUINOLIN-4-YL)AMINO]PENTYL-ETHYL-AMINO]ETHANOL, SULFURIC ACID, HYDROXYCHLOROQUINE SULPHATE
Route of administration: ORAL
Max daily dose: 5 mg/kg milligram(s)/kilogram
Max total dose: 21875 mg/kg milligram(s)/kilogram
Max treatment duration: 625 Week(s)
Authorisation status: Authorised
ATC code: P01BA02 — HYDROXYCHLOROQUINE
Marketing authorisation: -
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Auxiliary 4

Methotrexate Sodium

SCP10339494 · ATC

Active substance: Methotrexate Sodium
Substance synonyms: SODIUM METHOTREXATE, MTX SODIUM
Route of administration: SUBCUTANEOUS INJECTION
Max daily dose: 3.57 mg milligram(s)
Max total dose: 15625 mg milligram(s)
Max treatment duration: 625 Week(s)
Authorisation status: Authorised
ATC code: L01BA01 — METHOTREXATE
Marketing authorisation: -
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Methotrexate Sodium

SCP1034223 · ATC

Active substance: Methotrexate Sodium
Substance synonyms: SODIUM METHOTREXATE, MTX SODIUM
Route of administration: ORAL
Max daily dose: 3.57 mg milligram(s)
Max total dose: 15625 mg milligram(s)
Max treatment duration: 625 Week(s)
Authorisation status: Authorised
ATC code: L04AX03 — METHOTREXATE
Marketing authorisation: -
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Azathioprine

SCP102632035 · ATC

Active substance: Azathioprine
Route of administration: ORAL
Max daily dose: 2.5 mg/kg milligram(s)/kilogram
Max total dose: 10938 mg/kg milligram(s)/kilogram
Max treatment duration: 625 Week(s)
Authorisation status: Authorised
ATC code: L04AX01 — AZATHIOPRINE
Marketing authorisation: -
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Leflunomide

SUB08424MIG · Substance

Active substance: Leflunomide
Pharmaceutical form: TABLET
Route of administration: ORAL
Max daily dose: 20 mg milligram(s)
Max total dose: 87500 mg milligram(s)
Max treatment duration: 625 Week(s)
Authorisation status: Authorised
ATC code: - — -
Marketing authorisation: -
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Karolinska Institutet

Sponsor organisation: Karolinska Institutet
Address: Nobels Vag 6
City: Solna
Postcode: 171 65
Country: Sweden

Scientific contact point

Organisation: Karolinska Institutet
Contact name: Prof Ronald van Vollenhoven

Public contact point

Organisation: Karolinska Institutet
Contact name: Prof Ronald van Vollenhoven

Locations

4 EU/EEA countries · 25 investigational sites

By country

Country	MS status	Planned subjects	Sites
Denmark	Authorised, recruitment pending	182	7
Iceland	Authorised, recruitment pending	16	1
Norway	Authorised, recruitment pending	114	5
Sweden	Authorised, recruitment pending	393	12
Rest of world	—	0	—

Investigational sites

Denmark

7 sites · Authorised, recruitment pending

Odense University Hospital

Medicinsk afdeling, Baagoees Alle 15, 5700, Svendborg

Aarhus University Hospital

Led- og Bindevævssygdomme, Palle Juul-Jensen Blvd 99, 8200, Aarhus N

Odense University Hospital

Reumatologisk Afdeling C, J B Winsloews Vej 4, 5000, Odense C

Dansk Gigthospital

Reumatologisk Afdeling, Engelshøjgade 9A, Denmark, Sønderborg

Regionshospitalet Silkeborg

Diagnostic center, Falkevej 1A, 8600, Silkeborg

Aalborg Universitetshospital

Reumatologisk Afdeling, Reumatologisk afdeing, Reberbansgade 15, Aalborg

Rigshospitalet Glostrup

Afdeling for Rygkirurgi, Led- og Bindevævssygdomme, COPECARE, Valdemar Hansens Vej 1-23, 2600, Glostrup

Iceland

1 site · Authorised, recruitment pending

Landspitali

Centre for Rheumatology Research, Hringbraut 101, 101, Reykjavik

Norway

5 sites · Authorised, recruitment pending

Diakonhjemmet Sykehus AS

Department of Rheumatology, Diakonveien 12, 0370, Oslo

Universitetssykehuset Nord-Norge HF

Nevro-, Hud og Revmatologisk avdeling, Sykehusvegen 38, 9019, Tromsoe

St. Olavs Hospital HF

Department of Rheumatology, P. O. Box 3250, Torgarden, Trondheim

Helse Bergen HF

Department of Rheumatology, P. O. Box 1400, 5021, Bergen

Helse Moere Og Romsdal HF

Department of Rheumatology, Aasehaugen 5, 6017, Aalesund

Sweden

12 sites · Authorised, recruitment pending

Karolinska University Hospital

Department of Gastroenterology, Dermatology and Rheumatology, Eugeniavagen 3, 171 64, Solna

Karolinska University Hospital

Department of Gastroenterology, Dermatology and Rheumatology, Halsovagen, Flemingsberg, Huddinge

Universitetssjukhuset i Linköping

Reumatologiska kliniken, Universitetssjukhuset, Linköping, Linköping

Västmanlands sjukhus Västerås

Reumatologmottagningen, Västmanlands sjukhus Västerås, 721 89, Västerås

Skånes Universitetssjukhus, Malmö

Reumatologimottagning Malmö, Jan Waldenströms gata 1B, 20502, Malmö

Falu lasarett

Reumatologimottagning Falun, Falu lasarett Reumatologi, 79182, Falun

Centrum för reumatologi

Centrum för reumatologi, Norrbackagatan 90, 113 65, Stockholm

Sahlgrenska Universitetssjukhuset

Reumatologen Sahlgrenska Universitetssjukhuset/Sahlgrenska, Gröna Stråket 14, 41319, Göteborg

Universitetssjukhuset Örebro

Reumatologmottagningen Universitetssjukhuset Örebro, Universitetssjukhuset Örebro, 701 85, Orebro

Skånes Universitetssjukhus, Lund

Reumatologimottagning Lund, Kioskgatan 5, Reumatologimottagning Lund, Lund

Akademiska sjukhuset

Reumatologmottagningen, Akademiska sjukhuset, 751 85, Uppsala

Reumatologen Sahlgrenska Universitetssjukhuset/Mölndal

Reumatologen Sahlgrenska Universitetssjukhuset/Mölndal, Göteborgsvägen 31, 43130, Mölndal

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 24 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Type	Title	Version
Protocol (for publication)	NORD-STAR protocol	8
Recruitment arrangements (for publication)	CTIS placeholder	1
Recruitment arrangements (for publication)	CTIS Placeholder Document	1
Recruitment arrangements (for publication)	K1_ Recruitment arrangements placeholder	1
Recruitment arrangements (for publication)	Recruitment arrangements placeholder	1
Subject information and informed consent form (for publication)	Informeret samtykke til patientinformation v 4.1	1
Subject information and informed consent form (for publication)	L1_SIS and ICF description adults	0.9
Subject information and informed consent form (for publication)	L1_SIS and ICF description adults initial	1.2
Subject information and informed consent form (for publication)	NORD-STAR forlngelse_patientinformation og samtykkeerklring	1
Subject information and informed consent form (for publication)	NORD-STAR_deltagerinformation v 4.1	1
Subject information and informed consent form (for publication)	NORDSTAR_Patientinformation_Samtycke	2.3
Subject information and informed consent form (for publication)	Nr12a-Uppllysingarbla	1
Subject information and informed consent form (for publication)	Nr12b-Viauki	1
Subject information and informed consent form (for publication)	Nr12c-Samthykkisyfirlysing	1
Subject information and informed consent form (for publication)	Patientinformation_Samtycke_NORD-STAR uppfoljningsstudie	1
Subject information and informed consent form (for publication)	Upplystsam-vibot-NORDSTAR-nov2023	1
Summary of Product Characteristics (SmPC) (for publication)	Cimzia 200 mg solution for injection in pre-filled syringe Summary of Product Characteristics SmPC	1
Summary of Product Characteristics (SmPC) (for publication)	Hydroxychloroquine Summary of Product Characteristics SmPC	1
Summary of Product Characteristics (SmPC) (for publication)	ORENCIA 125 mg solution for injection pre-filled syringe	1
Summary of Product Characteristics (SmPC) (for publication)	Prednisolone 5mg Tablets Summary of Product Characteristics SmPC	1
Summary of Product Characteristics (SmPC) (for publication)	RoActemra 162 mg Solution for Injection in Pre-Filled Syringe SmPC	1
Summary of Product Characteristics (SmPC) (for publication)	RoActemra 20mg_ml Concentrate for Solution for Infusion Summary of Product Characteristics SmPC	1
Summary of Product Characteristics (SmPC) (for publication)	Salazopyrin En-Tabs 500 mg gastro-resistant tablets Summary of Product Characteristics SmPC	1
Summary of Product Characteristics (SmPC) (for publication)	Triamcinolone Hexacetonide	1

Application history

1 submissions — initial application plus substantial / non-substantial modifications

#	Type	Code	Submitted	Reference MS	Conclusion	Decision date
1	INITIAL	IN	2024-10-11	Sweden	Acceptable 2024-11-12	2024-11-12