This study has been transitioned to CTIS with ID 2024-516770-29-00 check the CTIS register for the current data. The objective of this study is to evaluate the clinical efficacy, biological effects and safety of anifrolumab treatment in pSS.
ID
Source
Brief title
Condition
- Autoimmune disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The selected primary outcome measure is the Composite of Relevant Endpoints for
Sjögren*s Syndrome (CRESS) response at week 24. The CRESS is a recently
developed composite endpoint which consists of five clinically relevant items
for pSS: a systemic disease activity, patient-reported symptoms, tear gland,
salivary gland and serology item. A CRESS responder is someone who reached
response on at least three out of five items.
Secondary outcome
1. Safety (adverse events and tolerability) of anifrolumab by monitoring
serious adverse events (SAE) and AE, treatment discontinuation related to SAE
and AE, and lab abnormalities at weeks 0, 4, 8, 12, 16, 20 and 24.
2. Total CRESS response at week 12
3. Individual CRESS items (continuous): Clinical EULAR Sjögren's Syndrome
Disease Activity Index (ESSDAI) (weeks 0, 8, 12, 20, 24), EULAR Sjögren's
Syndrome Patient Reported Index (ESSPRI) (weeks 0, 8, 12, 20, 24), Schirmer*s
test (weeks 0, 12, 24), Ocular Staining Score (OSS) (weeks 0, 12, 24),
unstimulated whole salivary flow (UWS) (weeks 0, 12, 24), Salivary gland
ultrasonography (SGUS) (Hocevar score) (weeks 0, 12, 24), rheumatoid factor
(RF) and total IgG concentration in blood (weeks 0, 8, 12, 20, 24).
4. ESSDAI (continuous) (weeks 0, 8, 12, 20, 24)
5. The (Clin)ESSDAI minimal clinically important improvement (MCII, defined as
decrease of >=3 points) and low disease activity (LDA, defined as score<5)
(weeks 8, 12, 20, 24)
6. Physician global disease activity (GDA) (weeks 0, 8, 12, 20, 24)
7. NRS score oral, ocular, and vaginal dryness and mental fatigue (weeks 0, 8,
12, 20, 24)
8. Patient GDA (weeks 0, 8, 12, 20, 24)
9. Short form-36 (SF-36) health survey (weeks 0, 12, 24)
10. EuroQoL-5 dimensions (EQ-5D) measure of health-related quality of life
(weeks 0, 8, 12, 20, 24)
11. Multidimensional Fatigue Index (MFI) scale (weeks 0, 12, 24)
12. Female Sexual Function Index (FSFI) in females (weeks 0, 12, 24)
13. Stimulated whole salivary flow (SWS) (weeks 0, 12, 24)
14. SGUS OMERACT score (weeks 0, 12, 24)
15. Parotid gland histology at baseline vs. week 24: focus score and area
fraction of CD45+ infiltrate
16. Serum levels of anti-SSA/-SSB, complement (C3/C4), lymphocyte count, and
presence of cryoglobulinemia (weeks 0, 8, 12, 20, 24)
Background summary
We aim to evaluate safety and determine the effects of anifrolumab on essential
clinical and biological parameters in patients with primary Sjögren*s syndrome
(pSS). Although the pathogenesis of pSS has not been fully elucidated, one of
the key immune pathways involved is type-I IFN signalling. Since anifrolumab is
a fully human, IgG1* monoclonal antibody to type-I interferon receptor subunit
1, we hypothesize that inhibition of type-I IFN signalling by anifrolumab may
reduce glandular and systemic inflammation and attenuate disease activity in
patients with pSS.
Study objective
This study has been transitioned to CTIS with ID 2024-516770-29-00 check the CTIS register for the current data.
The objective of this study is to evaluate the clinical efficacy, biological
effects and safety of anifrolumab treatment in pSS.
Study design
This study is a randomized, double-blind, placebo-controlled phase IIa
proof-of-mechanism trial. Thirty patients are randomized in a 2:1 ratio to
either anifrolumab or placebo treatment, with which they will be treated for 24
weeks.
Intervention
Anifrolumab vs. placebo treatment. Anifrolumab 300 mg will be administered in
intravenous infusions, once per 4 weeks, for a total treatment duration of 24
weeks. In total, participants will have 6 infusions during the study.
Study burden and risks
Primary SS has a major impact on patients* daily life. Apart from symptoms and
extraglandular manifestations related to pSS, patients may also be restricted
in their activities and their participation in society, resulting in a reduced
HR-QoL and an impaired socioeconomic status. Consequently, there is a great
need for developing adequate treatment modalities to reduce pSS-related
complaints and to intervene in the progression of SS. Despite a number of
recent, large RCTs with several promising (biological) drugs for pSS, no phase
III trial was able to demonstrate beneficial treatment effects compared to
placebo. This means that an unmet need for effective therapies in pSS remains
and that there is a need to develop new treatment interventions. Both patients
and physicians are willing to contribute to research to find effective
therapies for pSS.
We realize that this study protocol is intensive with frequent visits to the
outpatient clinic and consequently several tests, including parotid gland
biopsies, and that certain risks (SAEs or AEs) are involved in this treatment.
The most common side effects of anifrolumab according to the RCTs conducted in
systemic lupus erythematosus (SLE) are upper respiratory tract infection,
nasopharyngitis, infusion-related reaction, bronchitis and herpes zoster.
However, an imbalance in adverse events between anifrolumab and placebo has not
been observed in the previous trials. However, we assume, based on clinical
experience and the available literature on anifrolumab in SLE and what we know
of the underlying pathogenesis of pSS, that the advantages of participation in
this trial outweigh the burden and risks involved with this treatment. Based on
the rationale of this study and the experience with anifrolumab in SLE, we
expect a positive effect of anifrolumab on pSS. Furthermore, patients may take
advantage of close monitoring during this trial (e.g. information, support,
early treatment of symptoms and extraglandular manifestations, early detection
of possible MALT lymphomas).
Hanzeplein 1
Groningen 9713 GZ
NL
Hanzeplein 1
Groningen 9713 GZ
NL
Listed location countries
Age
Inclusion criteria
- Written informed consent.
- Female or male aged >= 18 years.
- Disease duration <= 10 years.
- Fulfillment of the 2016 ACR/EULAR classification criteria for primary
Sjögren's syndrome.
- ESSDAI >=5 and/or ESSPRI >=5. ESSDAI >=5 implicates a moderate to high
systemic disease activity and ESSPRI >=5 implicates that the patient-reported
symptom state is unacceptable. At least 50% of patients need to fulfil the
ESSDAI >=5 criterion. Inclusion of patients with low ESSDAI (<5) should be
discontinued when 50% have a low ESSDAI.
- Willingness to undergo a repeated biopsy. Baseline biopsy <=1 year before
inclusion and follow-up biopsy 24 weeks after start treatment.
- Use of reliable method of contraception for participants of reproductive
potential.
- Fully vaccinated against SARS-CoV-2, based on the current vaccine
recommendations for immunocompromised patients.
- Weight of >= 40 kg.
Exclusion criteria
- Presence of any other connective tissue disease.
- Positive pregnancy test at screening or breastfeeding.
- History of alcohol or drug abuse.
- History of malignancy or with a current suspicion for cancer, apart from
local MALT lymphoma, squamous or basal cell carcinoma of the skin treated with
documented success of curative therapy <=3 months prior to week 0 or cervical
cancer in situ treated with apparent success with curative therapy <=1 years
prior to week 0.
- Subjects with evidence (as assessed by the investigator) of active or latent
bacterial or viral infections at the time of potential enrollment, including
subjects with evidence of HIV which will be tested during screening.
- History of chronic or recurrent serious infections.
- Subjects who have received any live or attenuated vaccines within 8 weeks
prior to signing the ICF.
- Blood transfusion or receipt of blood products within 4 weeks prior to
signing the ICF.
- Underlying cardiac, pulmonary, metabolic, renal, hepatic, gastrointestinal,
hematological or neurological conditions, chronic or latent infectious diseases
or immune deficiency which places the patient at an unacceptable risk for
participation in this study.
- Preceding treatment with biological DMARDs, including abatacept, anti-TNF or
other monoclonal antibodies within 6 months, and rituximab within 12 months
from baseline.
- Use of high-dose prednisone, less than 2 weeks before inclusion. Stable low
dose (<= 10 mg) is allowed.
- Use of hydroxychloroquine, methotrexate, cyclophosphamide, cyclosporine,
azathioprine, MMF and leflunomide less than 3 months ago.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2024-516770-29-00 |
| EudraCT | EUCTR2022-000609-28-NL |
| CCMO | NL80976.042.22 |