Determine Effectiveness of Anifrolumab In SYstemic Sclerosis (DAISY)

Systemic Sclerosis Clinical Trial

— DAISY  

Official title:

A Multicenter, Randomized, Parallel-group, Double-blind,Two-arm Phase III Study to Evaluate the Safety and Efficacy of Anifrolumab Compared With Placebo in Male and Female Participants 18 to 70 Years of Age Inclusive With Systemic Sclerosis

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05925803
• Other study ID #: D3460C00002
• Secondary ID: 2023-505976-31
• Status: Recruiting
• Phase: Phase 3
• Start date: November 8, 2023
• Est. completion date: December 31, 2027

Study information

• Verified date: December 2023
• Source: AstraZeneca
• Contact: AstraZeneca Clinical Study Information Center
• Phone: 1-877-240-9479
• Email: information.center[@]astrazeneca.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to evaluate the efficacy and safety of treatment with subcutaneous anifrolumab versus placebo in adult participants with systemic sclerosis. The target population for this study includes patients who meet the 2013 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification for systemic sclerosis, either limited or diffuse cutaneous subsets, with a disease duration of less than 6 years from first non-Raynaud's phenomenon symptom.

Description:

This is a multicenter, randomized, double-blind, placebo-controlled, Phase III study to evaluate the efficacy and safety of anifrolumab in the treatment of adult participants with Systemic Sclerosis (SSc) who may be taking one or a combination of protocol-specified standard therapies. The use of one of the following standard immunosuppressant therapies is permitted at a stable dose, but not mandated: hydroxychloroquine, mycophenolate mofetil (MMF), mycophenolic acid or mycophenolate sodium (MPA), methotrexate, azathioprine, tacrolimus, and oral glucocorticoids. MMF or MPA, azathioprine, and methotrexate may be used in combination with hydroxychloroquine and/or low-dose oral glucocorticoids [≤ 10 mg/day]. Approximately 306 eligible participants will be randomized in a 1:1 ratio to receive either 120 mg anifrolumab (or matching placebo) given subcutaneously once weekly for 52 weeks. The study will be stratified by the following factors: - Interstitial lung disease (ILD) (yes, no) at Week 0 (Day1); - MMF or MPA use (yes ,no) at Week 0 (Day 1); and - Disease duration, defined as the time from the first non-Raynaud's symptom attributable to SSc (<18 months, ≥ 18 months) at Week 0 (Day 1) Study treatment will be administered subcutaneously via an accessorized prefilled syringe by study staff or by the participant or carer, either in the clinic or at home, with most doses being administered at home. The study consists of 4 periods: a 6-week screening period, a 52-week, double-blind, placebo-controlled period, a 52-week open-label active treatment period, and a 12-week safety follow-up period. There are a total of 16 study visits with most visits in the treatment period occurring every 8 to 12 weeks. The periods are described below: - Screening Period: This may involve one or more visits to the study site. - Double Blind Treatment Period: Treatment Period when participants will receive once weekly injections of anifrolumab or matching placebo. Participation will involve in-clinic study visits at Weeks 0 (Day 1), 1, 4, 8*, 16, 24, 36, 48 and 52. *The visit at Week 8 may be either by telephone or in person. - Open Label Treatment Period: At Week 52, all participants will be given anifrolumab 120 mg (subcutaneous) once weekly for 52 weeks (last dose at Week 103). Participation will involve in-clinic study visits at Weeks 52, 56, 64, 76. 88 and 104. - Safety Follow-up Period: All participants will return to the clinic for a 12-week post treatment visit. This will occur post Double Blind Treatment Period (Week 52 or Double Blind Period early discontinuation) or post Open Label Treatment Period (Week 104 or Open Label Period early discontinuation).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 306
• Est. completion date: December 31, 2027
• Est. primary completion date: October 9, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

Key Inclusion Criteria:

1. Adult patients from 18 to 70 years of age inclusive

2. Systemic sclerosis according to 2013 ACR/EULAR classification criteria

3. Limited or diffuse cutaneous subsets

4. Systemic sclerosis disease duration within 6 years from first non-Raynaud's phenomenon manifestation

5. Either HAQ-DI score = 0.25 points or PtGA score = 3 points

6. mRSS > 10 with early disease or rapid progression as defined by the protocol

7. mRSS = 15 with disease duration = 18 months and active disease as defined by the protocol

8. Stable background therapies can be used including hydroxychloroquine, methotrexate, azathioprine, mycophenolate mofetil, mycophenolic sodium, mycophenolic acid, oral glucocorticoids or tacrolimus

9. Women of childbearing potential with a negative urine pregnancy test

10. Uninvolved skin at injection sites

Key Exclusion Criteria:

1. Anticentromere antibody seropositivity on central laboratory

2. Severe cardiopulmonary disease as defined by the protocol

3. History of systemic sclerosis renal crisis within past 12 months (estimated glomerular filtration rate(eGFR) < 45 mL/min)

4. Overlap syndromes, systemic lupus erythematosus with anti-double-stranded deoxyribonucleic acid antibody seropositivity or anti-citrullinated protein antibodies-positive rheumatoid arthritis, or SSc mimics (eg, scleromyxedema, eosinophilic fasciitis)

5. History of, or current, any other inflammatory diseases, eg, inflammatory bowel disease, skin disease, that, in the opinion of the investigator, could interfere with efficacy and safety assessments or require immunomodulatory therapy

6. Evidence of moderately severe concurrent nervous system, renal, endocrine, hepatic (eg, underlying chronic liver disease [Child Pugh A, B, C hepatic impairment]), or gastrointestinal disease (eg, clinical signs of malabsorption or needing parenteral nutrition) not related to SSc, as determined by the investigator

7. Hematopoietic stem cell transplantation or solid organ/limb transplantation

8. Any severe case of Herpes Zoster infection as defined by the protocol

9. Known malignancy or a history of malignancy within 5 years, with exception of excised/cured local basal or squamous cell carcinoma of the skin or carcinoma in situ of the uterine cervix

10. Major surgery within 8 weeks prior to and/or during study enrollment

11. Known active current or history of recurrent infections

12. Severe cardiopulmonary disease

13. Any condition that, in the opinion of the investigator or AstraZeneca, would interfere with the efficacy or safety evaluation of the study intervention or put participant at safety risk

Related Conditions & MeSH terms

• Scleroderma
• Scleroderma, Diffuse
• Scleroderma, Systemic
• Sclerosis
• Systemic Sclerosis

Intervention

Biological:
• Anifrolumab (blinded)
Anifrolumab treatment delivered subcutaneously, once weekly for 52 weeks

Drug:
• Placebo (blinded)
matched placebo delivered subcutaneously, once weekly for 52 weeks

Biological:
• Anifrolumab (unblinded, open label)
At Week 52, all patients will receive Anifrolumab subcutaneously once weekly for 52 weeks

Locations

Country	Name	City	State
Austria	Research Site	Graz
Austria	Research Site	Innsbruck
Austria	Research Site	Linz
Austria	Research Site	Wien
Belgium	Research Site	Brussels
Belgium	Research Site	Gent
Belgium	Research Site	Leuven
Canada	Research Site	Calgary	Alberta
Canada	Research Site	Halifax	Nova Scotia
Canada	Research Site	Montreal	Quebec
Canada	Research Site	Montreal	Quebec
Canada	Research Site	Quebec
Canada	Research Site	Toronto	Ontario
Canada	Research Site	Vancouver	British Columbia
China	Research Site	Beijing
China	Research Site	Beijing
China	Research Site	Chengdu
China	Research Site	Guangzhou
China	Research Site	Guangzhou
China	Research Site	Hangzhou
China	Research Site	Lanzhou
China	Research Site	Shanghai
China	Research Site	Shanghai
China	Research Site	Tianjin
China	Research Site	Wuhan
France	Research Site	Bordeaux Cedex
France	Research Site	Brest Cedex
France	Research Site	La Tronche
France	Research Site	Paris
France	Research Site	Paris
France	Research Site	Paris
France	Research Site	Reims
France	Research Site	Rennes Cedex 9
France	Research Site	Strasbourg Cedex
France	Research Site	Toulouse
Germany	Research Site	Bad Bramstedt
Germany	Research Site	Berlin
Germany	Research Site	Düsseldorf
Germany	Research Site	Freiburg
Germany	Research Site	Köln
Germany	Research Site	Mainz
Germany	Research Site	Minden
Germany	Research Site	München
Germany	Research Site	Münster
Germany	Research Site	Tübingen
Hungary	Research Site	Budapest
Hungary	Research Site	Debrecen
Hungary	Research Site	Pécs
Hungary	Research Site	Szeged
India	Research Site	Ahmedabad
India	Research Site	Ahmedabad
India	Research Site	Delhi
India	Research Site	Gurugram
India	Research Site	Hyderabad
India	Research Site	Kolkata
India	Research Site	Mumbai
India	Research Site	Mumbai
India	Research Site	Mysuru
India	Research Site	New Delhi
India	Research Site	Pune
India	Research Site	Secunderabad
India	Research Site	Visakhapatnam
Israel	Research Site	Afula
Israel	Research Site	Hadera
Israel	Research Site	Haifa
Israel	Research Site	Haifa
Israel	Research Site	Jerusalem
Israel	Research Site	Kfar-Saba
Israel	Research Site	Ramat Gan
Italy	Research Site	Ancona
Italy	Research Site	Brescia
Italy	Research Site	Cona
Italy	Research Site	Firenze
Italy	Research Site	Milano
Italy	Research Site	Milano
Italy	Research Site	Monserrato
Italy	Research Site	Napoli
Italy	Research Site	Padova
Italy	Research Site	Roma
Italy	Research Site	Roma
Italy	Research Site	Roma
Japan	Research Site	Bunkyo-ku
Japan	Research Site	Iruma-Gun
Japan	Research Site	Kanazawa-shi
Japan	Research Site	Maebashi-shi
Japan	Research Site	Nagasaki-shi
Japan	Research Site	Nagoya-shi
Japan	Research Site	Sapporo-shi
Japan	Research Site	Sendai-shi
Japan	Research Site	Shinjuku-ku
Japan	Research Site	Shinjuku-ku
Japan	Research Site	Suita-shi
Japan	Research Site	Takatsuki-shi
Japan	Research Site	Toyoake-shi
Japan	Research Site	Yokohama-shi
Korea, Republic of	Research Site	Busan
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Mexico	Research Site	Cdmx
Mexico	Research Site	Chihuahua
Mexico	Research Site	Ciudad de Mexico
Mexico	Research Site	Guadalajara
Mexico	Research Site	Guadalajara
Mexico	Research Site	México
Mexico	Research Site	San Luis Potosi
Mexico	Research Site	San Luis Potosi
Mexico	Research Site	San Luis Potosí
Netherlands	Research Site	Amsterdam
Netherlands	Research Site	Groningen
Netherlands	Research Site	Leiden
Poland	Research Site	Bialystok
Poland	Research Site	Bydgoszcz
Poland	Research Site	Krakow
Poland	Research Site	Kraków
Poland	Research Site	Kraków
Poland	Research Site	Poznan
Poland	Research Site	Warszawa
Romania	Research Site	Bucuresti
Romania	Research Site	Cluj Napoca
Romania	Research Site	Iasi
South Africa	Research Site	Parktown
South Africa	Research Site	Pretoria
Spain	Research Site	Barcelona
Spain	Research Site	Barcelona
Spain	Research Site	La Coruna
Spain	Research Site	Madrid
Spain	Research Site	Malaga
Spain	Research Site	Valencia
Spain	Research Site	Valencia
Spain	Research Site	Vigo
Turkey	Research Site	Ankara
Turkey	Research Site	Antalya
Turkey	Research Site	Basaksehir
Turkey	Research Site	Kocaeli
Turkey	Research Site	Merkez
United Kingdom	Research Site	Cannock
United Kingdom	Research Site	Leeds
United Kingdom	Research Site	London
United Kingdom	Research Site	Manchester
United Kingdom	Research Site	Sheffield
United States	Research Site	Allen	Texas
United States	Research Site	Ann Arbor	Michigan
United States	Research Site	Atlanta	Georgia
United States	Research Site	Babylon	New York
United States	Research Site	Baltimore	Maryland
United States	Research Site	Birmingham	Alabama
United States	Research Site	Boca Raton	Florida
United States	Research Site	Chicago	Illinois
United States	Research Site	Cincinnati	Ohio
United States	Research Site	Gainesville	Florida
United States	Research Site	Houston	Texas
United States	Research Site	Jacksonville	Florida
United States	Research Site	Jacksonville	Florida
United States	Research Site	Kansas City	Kansas
United States	Research Site	Los Angeles	California
United States	Research Site	Los Angeles	California
United States	Research Site	Miami	Florida
United States	Research Site	Minneapolis	Minnesota
United States	Research Site	New Orleans	Louisiana
United States	Research Site	New York	New York
United States	Research Site	North Haven	Connecticut
United States	Research Site	Orange	California
United States	Research Site	Rochester	Minnesota
United States	Research Site	San Diego	California
United States	Research Site	Scottsdale	Arizona
United States	Research Site	Shreveport	Louisiana
United States	Research Site	Tamarac	Florida
United States	Research Site	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
AstraZeneca

Countries where clinical trial is conducted

United States,  Austria,  Belgium,  Canada,  China,  France,  Germany,  Hungary,  India,  Israel,  Italy,  Japan,  Korea, Republic of,  Mexico,  Netherlands,  Poland,  Romania,  South Africa,  Spain,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of participants responding to treatment based on the Revised Composite Response Index in Systemic Sclerosis (CRISS-25)	Number of participants meeting all the criteria: Improvement in at least 2 components (=5% increase for percent predicted Forced Vital Capacity (FVC) and/or=25% decrease for Modified Rodnan Skin Score (mRSS), Health Assessment Questionnaire Disability Index (HAQ-DI), Patient Global Assessment (PtGA), Clinician Global Assessment (CGA); Worsening in no more than one component (=5% decrease percent predicted FVC and/or=25% increase for mRSS, HAQ-DI, PtGA, CGA); No significant SSc-related event as defined by: New scleroderma renal crisis New decline in percent predicted FVC=15% in established interstitial lung disease or new percent predicted FVC below 80% predicted New onset of left ventricular failure requiring treatment New onset of pulmonary arterial hypertension requiring treatment Gastrointestinal dysmotility requiring enteral or parenteral nutrition Digital ischemia with gangrene, amputation, or hospitalization requiring treatment; -Otherwise, a participant is a non-responder	at Week 52
Secondary	Change from baseline in mRSS	Change from baseline in mRSS score. The mRSS scoring ranges from 0 (normal) to 51 (severe).	at Week 52
Secondary	Number of patients with improvement in individual revised Composite Response Index in Systemic Sclerosis (CRISS-25)	Number of participants who have improvements in the following improvement components, evaluated separately: = 5% increase in percent predicted Forced Vital Capacity (FVC); = 25% decrease in mRSS; = 25% decrease in HAQ-DI; =25% decrease in PtGA; =25% decrease in CGA	at Week 52
Secondary	Change from baseline in chest computed tomography imaging	Change from baseline in quantitative interstitial lung disease score	at Week 52
Secondary	Change from baseline in Scleroderma Skin Patient Reported Outcome	Change from baseline in the Scleroderma Skin Patient Reported Outcome scores	at Week 52
Secondary	Change from baseline in FVC	Change from baseline in FVC (ml) in patients with interstitial lung disease; Change from baseline in FVC (ml) in all patients	at Week 52
Secondary	Change from baseline in percent predicted FVC	Change from baseline in percent predicted FVC in patients with interstitial lung disease; Change from baseline in percent predicted FVC in all patient	at Week 52
Secondary	Anifrolumab pharmacokinetic parameters in serum	Anifrolumab serum concentrations will be summarised using descriptive statistics at each visit. Due to sparse pharmacokinetic sampling, the pharmacokinetic assessment will be primarily based on observed serum trough concentrations (Ctrough)	Weeks 4, 16, 24, 36, 52, 56, 76, and 104 to follow-up (max 116 weeks)
Secondary	Anifrolumab pharmacodynamics via changes in type I IFN 21-gene signature generated from blood	Type I Interferon inducible gene signature will be assessed by a 21-gene assay in whole blood. The suppression of the type I IFN 21-gene signature will be showed as a percent of baseline through study completion, during both the double-blind treatment and open label periods.	Double-blind treatment period: pre-dose (Day 1) Weeks 4, 16, 24, 52; open-label period: weeks 56, 76 and 104
Secondary	Prevalence of anti-drug antibodies to Anifrolumab	Anti-drug antibodies and titer determination in anti-drug antibody positive participants. The presence of neutralizing anti-drug antibodies will also be tested in all anti-drug positive samples.	Weeks 4, 16, 24, 36, 52, 56, 76, and 104 to follow-up (max 116 weeks)
Secondary	Incidence of adverse events	Adverse events (non-serious, serious, and adverse event of special interest (AESI)) are assessed as variables of safety and tolerability of anifrolumab.; The AESIs are non-opportunistic serious infections, opportunistic infections, malignancy, herpes zoster, Tuberculosis (TB) (including latent TB), injection site reactions, and major adverse cardiac events.	From screening to follow-up (max 126 weeks)
Secondary	Incidence of abnormal vital signs	Change from baseline of pulse rate, blood pressure, respiration rate, and body temperature will be assessed by visit and treatment group including participants with treatment-emergent changes.	From screening to follow-up (max 126 weeks)
Secondary	Incidence of abnormal laboratory parameters	Changes from baseline in haematology, clinical chemistry and lipid variables will be assessed by visit and treatment including participants with treatment-emergent changes.	From screening to follow-up (max 126 weeks)
Secondary	Incidence of abnormal ECG findings	Observed values of heart rate, QRS duration, PR interval, RR interval and QT interval will be summarised by visit and treatment group including participants with clinically significant abnormal results.	From screening to end of treatment visit (max 110 weeks)
Secondary	Incidence of abnormal physical exam findings	Changes from baseline in weight (kilograms) will be assessed by visit and treatment and medically significant changes from the screening physical examination will be recorded as adverse events.	From screening to follow-up (max 126 weeks)
Secondary	Number of subjects with suicidal ideation and behavior and suicide attempts via Columbia-Suicide Severity Rating Scale (C-SSRS)	The C-SSRS is used to assess suicidal ideation, behavior, and suicide on a graded scale from 1 to 5. 1 indicates as low suicidal and 5 as high suicidal behavior.	From screening to follow-up (max 126 weeks)
Secondary	Total score of Personal Health Questionnaire Depression Scale-8 (PHQD-8)	PHQ-8 is an 8-item self-report scale, all items are rated on a score of 0-3, for a total range of 0-24. PHQD-8 assesses symptoms of depression over the previous 2 weeks. Higher scores indicate more depressive symptoms.	From screening to follow-up (max 126 weeks)