Determine Effectiveness of Anifrolumab In SYstemic Sclerosis (DAISY)

• Sponsor: AstraZeneca (Industry)
• Overall Status: Not yet recruiting
• CT.gov ID: NCT05925803
• Collaborator: (none)
• Enrollment: 306
• Locations: 131
• Arms: 2
• Anticipated Duration (Months): 53.6
• Patients Per Site: 2.3
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Systemic Sclerosis; Scleroderma	Biological: Anifrolumab (blinded); Drug: Placebo (blinded); Biological: Anifrolumab (unblinded, open label)	Phase 3

Detailed 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).

Study Design

• Study Type: Interventional
• Anticipated Enrollment: 306 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Subjects will be randomized in a 1:1 ratio to either anifrolumab or matching placebo for 52 weeks (double blind treatment period). At Week 52, all patients will be treated with 120 mg Anifrolumab for 52 weeks (open label treatment period).Subjects will be randomized in a 1:1 ratio to either anifrolumab or matching placebo for 52 weeks (double blind treatment period). At Week 52, all patients will be treated with 120 mg Anifrolumab for 52 weeks (open label treatment period).
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Double blind period- masking -everyone will be masked to the treatment allocation during the first 52 weeks Open label period - no masking- beginning at week 52, all participants will receive Anifrolumab for 52 weeks. During the open label period, there is no masking of study treatment, however, the treatment that participants received in the double blind period (first 52 weeks) will remain masked until the end of the study.
• Primary Purpose: Treatment
• 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
• Anticipated Study Start Date: Jul 13, 2023
• Anticipated Primary Completion Date: Dec 31, 2027
• Anticipated Study Completion Date: Dec 31, 2027

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Anifrolumab (subcutaneous weekly injection) Anifrolumab subcutaneous injection once weekly	Biological: Anifrolumab (blinded); Anifrolumab treatment delivered subcutaneously, once weekly for 52 weeks; Other Names: Treatment arm (blinded) ; Biological: Anifrolumab (unblinded, open label); At Week 52, all patients will receive Anifrolumab subcutaneously once weekly for 52 weeks; Other Names: Treatment arm (not blinded)
Placebo Comparator: matched placebo control (subcutaneous weekly injection) matched placebo control subcutaneous injection once weekly	Drug: Placebo (blinded); matched placebo delivered subcutaneously, once weekly for 52 weeks; Other Names: Placebo arm (blinded)

Outcome Measures

Primary Outcome Measures

1. Number of participants responding to treatment based on the Revised Composite Response Index in Systemic Sclerosis (CRISS-25) [at Week 52]

   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

Secondary Outcome Measures

1. Change from baseline in mRSS [at Week 52]

   Change from baseline in mRSS score. The mRSS scoring ranges from 0 (normal) to 51 (severe).

2. Number of patients with improvement in individual revised Composite Response Index in Systemic Sclerosis (CRISS-25) [at Week 52]

   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

3. Change from baseline in chest computed tomography imaging [at Week 52]

   Change from baseline in quantitative interstitial lung disease score

4. Change from baseline in Scleroderma Skin Patient Reported Outcome [at Week 52]

   Change from baseline in the Scleroderma Skin Patient Reported Outcome scores

5. Change from baseline in FVC [at Week 52]

   Change from baseline in FVC (ml) in patients with interstitial lung disease Change from baseline in FVC (ml) in all patients

6. Change from baseline in percent predicted FVC [at Week 52]

   Change from baseline in percent predicted FVC in patients with interstitial lung disease Change from baseline in percent predicted FVC in all patient

7. Anifrolumab pharmacokinetic parameters in serum [Weeks 4, 16, 24, 36, 52, 56, 76, and 104 to follow-up (max 116 weeks)]

   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)

8. Anifrolumab pharmacodynamics via changes in type I IFN 21-gene signature generated from blood [Double-blind treatment period: pre-dose (Day 1) Weeks 4, 16, 24, 52; open-label period: weeks 56, 76 and 104]

   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.

9. Prevalence of anti-drug antibodies to Anifrolumab [Weeks 4, 16, 24, 36, 52, 56, 76, and 104 to follow-up (max 116 weeks)]

   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.

10. Incidence of adverse events [From screening to follow-up (max 126 weeks)]

    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.

11. Incidence of abnormal vital signs [From screening to follow-up (max 126 weeks)]

    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.

12. Incidence of abnormal laboratory parameters [From screening to follow-up (max 126 weeks)]

    Changes from baseline in haematology, clinical chemistry and lipid variables will be assessed by visit and treatment including participants with treatment-emergent changes.

13. Incidence of abnormal ECG findings [From screening to end of treatment visit (max 110 weeks)]

    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.

14. Incidence of abnormal physical exam findings [From screening to follow-up (max 126 weeks)]

    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.

15. Number of subjects with suicidal ideation and behavior and suicide attempts via Columbia-Suicide Severity Rating Scale (C-SSRS) [From screening to follow-up (max 126 weeks)]

    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.

16. Total score of Personal Health Questionnaire Depression Scale-8 (PHQD-8) [From screening to follow-up (max 126 weeks)]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Birmingham	Alabama	United States	35205
2	Research Site	Scottsdale	Arizona	United States	85259
3	Research Site	Los Angeles	California	United States	90095
4	Research Site	San Diego	California	United States	92108
5	Research Site	North Haven	Connecticut	United States	06473
6	Research Site	Washington	District of Columbia	United States	20007
7	Research Site	Boca Raton	Florida	United States	33486
8	Research Site	Jacksonville	Florida	United States	32216
9	Research Site	Jacksonville	Florida	United States	32224
10	Research Site	Chicago	Illinois	United States	60611
11	Research Site	Kansas City	Kansas	United States	66160
12	Research Site	New Orleans	Louisiana	United States	70121
13	Research Site	Shreveport	Louisiana	United States	71103
14	Research Site	Baltimore	Maryland	United States	21224
15	Research Site	Ann Arbor	Michigan	United States	48109
16	Research Site	Minneapolis	Minnesota	United States	55455
17	Research Site	Babylon	New York	United States	11702
18	Research Site	New York	New York	United States	10032
19	Research Site	Cincinnati	Ohio	United States	45267
20	Research Site	Houston	Texas	United States	77030
21	Research Site	Graz		Austria	8036
22	Research Site	Innsbruck		Austria	6020
23	Research Site	Wien		Austria	1090
24	Research Site	Brussels		Belgium	1070
25	Research Site	Gent		Belgium	B-9000
26	Research Site	Leuven		Belgium	3000
27	Research Site	Calgary	Alberta	Canada	T2N 4Z6
28	Research Site	Halifax	Nova Scotia	Canada	B3H 2Y9
29	Research Site	Toronto	Ontario	Canada	M5T 3L9
30	Research Site	Montreal	Quebec	Canada	H3T 1E2
31	Research Site	Montreal	Quebec	Canada	H4J 1C5
32	Research Site	Quebec		Canada	G1V 3M7
33	Research Site	Beijing		China	100191
34	Research Site	Beijing		China	CN-100730
35	Research Site	Chengdu		China	610041
36	Research Site	Guangzhou		China	510100
37	Research Site	Guangzhou		China	510530
38	Research Site	Shanghai		China	200032
39	Research Site	Shanghai		China	201210
40	Research Site	Tianjin		China	300052
41	Research Site	Wuhan		China	430022
42	Research Site	Bordeaux Cedex		France	33076
43	Research Site	Brest Cedex		France	29609
44	Research Site	La Tronche		France	38043
45	Research Site	Paris		France	75020
46	Research Site	Paris		France	75651
47	Research Site	Paris		France	75679
48	Research Site	Reims		France	51092
49	Research Site	Rennes Cedex 9		France	35033
50	Research Site	Strasbourg Cedex		France	67098
51	Research Site	Toulouse		France	31059
52	Research Site	Bad Bramstedt		Germany	24576
53	Research Site	Berlin		Germany	10117
54	Research Site	Düsseldorf		Germany	40225
55	Research Site	Freiburg		Germany	79106
56	Research Site	Köln		Germany	50937
57	Research Site	Mainz		Germany	55131
58	Research Site	München		Germany	80336
59	Research Site	Tübingen		Germany	72076
60	Research Site	Budapest		Hungary	1138
61	Research Site	Debrecen		Hungary	4032
62	Research Site	Pécs		Hungary	7632
63	Research Site	Szeged		Hungary	6725
64	Research Site	Afula		Israel	18101
65	Research Site	Haifa		Israel	31048
66	Research Site	Haifa		Israel	31096
67	Research Site	Kfar-Saba		Israel	4428164
68	Research Site	Ancona		Italy	60126
69	Research Site	Brescia		Italy	25123
70	Research Site	Cona		Italy	44124
71	Research Site	Firenze		Italy	50134
72	Research Site	Milano		Italy	20122
73	Research Site	Milano		Italy	20132
74	Research Site	Monserrato		Italy	09042
75	Research Site	Napoli		Italy	80131
76	Research Site	Padova		Italy	35128
77	Research Site	Roma		Italy	00128
78	Research Site	Roma		Italy	00161
79	Research Site	Roma		Italy	00168
80	Research Site	Bunkyo-ku		Japan	113-8603
81	Research Site	Iruma-Gun		Japan	350-0495
82	Research Site	Kanazawa-shi		Japan	920-8641
83	Research Site	Sapporo-shi		Japan	060-8638
84	Research Site	Sendai-shi		Japan	980-8574
85	Research Site	Shinjuku-ku		Japan	160-8582
86	Research Site	Shinjuku-ku		Japan	162-8666
87	Research Site	Suita-shi		Japan	565-0871
88	Research Site	Toyoake-shi		Japan	470-1192
89	Research Site	Yokohama-shi		Japan	236-0004
90	Research Site	Busan		Korea, Republic of	49241
91	Research Site	Seoul		Korea, Republic of	04401
92	Research Site	Seoul		Korea, Republic of	04763
93	Research Site	Seoul		Korea, Republic of	06591
94	Research Site	Seoul		Korea, Republic of	13620
95	Research Site	Cdmx		Mexico	06700
96	Research Site	Chihuahua		Mexico	31000
97	Research Site	Ciudad de Mexico		Mexico	11850
98	Research Site	Guadalajara		Mexico	44158
99	Research Site	Guadalajara		Mexico	44650
100	Research Site	México		Mexico	14000
101	Research Site	San Luis Potosi		Mexico	78213
102	Research Site	San Luis Potosi		Mexico	78290
103	Research Site	San Luis Potosí		Mexico	78250
104	Research Site	Groningen		Netherlands	9713 GZ
105	Research Site	Leiden		Netherlands	2300 RC
106	Research Site	Białystok		Poland	15-276
107	Research Site	Bydgoszcz		Poland	85-168
108	Research Site	Krakow		Poland	31-637
109	Research Site	Kraków		Poland	30-002
110	Research Site	Kraków		Poland	30-721
111	Research Site	Poznań		Poland	61-545
112	Research Site	Warszawa		Poland	00-874
113	Research Site	Bucuresti		Romania	011172
114	Research Site	Cluj Napoca		Romania	400006
115	Research Site	Iasi		Romania	700661
116	Research Site	Barcelona		Spain	08003
117	Research Site	Barcelona		Spain	08041
118	Research Site	La Coruna		Spain	15006
119	Research Site	Madrid		Spain	28041
120	Research Site	Malaga		Spain	29009
121	Research Site	Valencia		Spain	46017
122	Research Site	Valencia		Spain	46026
123	Research Site	Vigo		Spain	36214
124	Research Site	Ankara		Turkey	06100
125	Research Site	Antalya		Turkey	07059
126	Research Site	Merkez		Turkey	23200
127	Research Site	Cannock		United Kingdom	WS11 2XY
128	Research Site	Leeds		United Kingdom	LS7 4SA
129	Research Site	London		United Kingdom	NW3 2QG
130	Research Site	Manchester		United Kingdom	M13 9WL
131	Research Site	Sheffield		United Kingdom	S10 2JF

Sponsors and Collaborators

• AstraZeneca

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT05925803
• Other Study ID Numbers: D3460C00002; 2023-505976-31
• First Posted: Jun 29, 2023
• Last Update Posted: Jun 29, 2023
• Last Verified: Jun 1, 2023

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by AstraZeneca: Systemic Sclerosis (SSc); Scleroderma; Anifrolumab; Limited; Diffuse; Cutaneous; Interstitial lung disease (ILD); Autoimmune diseases; Immune system diseases; Immunosuppressants; Systemic Sclerosis interstitial lung disease (SSc- ILD)
• Additional relevant MeSH terms: Scleroderma, Systemic; Scleroderma, Diffuse; Sclerosis; Antibodies, Monoclonal

Study Results

No Results Posted as of Jun 29, 2023