Efficacy and Safety Evaluation of Dazodalibep in Patients with Moderate-to-Severe Systemic Sjögren’s Syndrome: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study
- Trial ID
- 2023-503904-10-00
- Protocol
- HZNP-DAZ-301
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the effect of **dazodalibep** on systemic manifestations in participants with Sjögren’s Syndrome (SS) who exhibit moderate-to-severe systemic disease activity. This is clinically relevant as it aims to address the systemic involvement in SS, which can significantly impact patient quality of life and disease progression.
Secondary objectives include:
- Evaluating the effect of dazodalibep on measures of systemic activity and patient-reported outcomes (PROs) in participants with SS.
- Assessing the impact of dazodalibep on salivary flow, which is a critical symptom in SS affecting oral health and comfort.
- Characterizing the pharmacokinetics (PK) of dazodalibep in this patient population to understand its absorption, distribution, metabolism, and excretion.
- Evaluating the safety and tolerability of multiple doses of dazodalibep, ensuring that the treatment is not only effective but also safe for long-term use.
Participants
The clinical trial involves a total of **423 participants** diagnosed with **Sjögren’s Syndrome** with moderate-to-severe systemic disease activity. The study population includes both male and female adults aged 18 years and older, with no upper age limit specified. Participants were selected based on their ability to provide informed consent and meet the 2016 American College of Rheumatology/EULAR Classification Criteria for Sjögren’s Syndrome. The trial includes individuals with an ESSDAI score of 5 or higher at screening, indicating significant disease activity. Participants are required to have either anti-Ro autoantibodies or rheumatoid factor present. Lifestyle considerations include the requirement for females of childbearing potential to use highly effective contraception methods, and all participants must be vaccinated against SARS-CoV-2 according to local guidelines. The trial also ensures that participants have no history of active tuberculosis and have a negative interferon gamma release assay test for TB at screening. The study population is considered vulnerable, reflecting the careful selection criteria to ensure participant safety and data integrity.
Plans and Procedures
The clinical trial is a **Phase 3 randomized, double-blind, placebo-controlled study** designed to evaluate the efficacy and safety of **Dazodalibep** in participants with **Sjögren’s Syndrome** with moderate-to-severe systemic disease activity. The trial aims to assess the effect of Dazodalibep on systemic manifestations of the disease. The study is expected to commence recruitment on March 4, 2024, and conclude by June 8, 2026, with a total duration of approximately 27 months.
Participants will be randomly assigned to receive either Dazodalibep or a placebo, both administered as a **solution for infusion**. The trial will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor progress and collect data, and a final end-of-study visit to assess outcomes. The primary endpoint is the change from baseline in the **ESSDAI score** at Week 48, with secondary endpoints including various measures of disease activity and patient-reported outcomes.
Participant involvement is expected to last up to 48 weeks, with conditions for early termination including adverse events, withdrawal of consent, or protocol non-compliance. The study will ensure that all participants meet specific inclusion criteria, such as being adults diagnosed with Sjögren’s Syndrome according to established criteria, and will exclude those with contraindications or other disqualifying conditions. The trial will adhere to rigorous scientific and ethical standards to ensure the validity and reliability of the results.
Treatment
The clinical trial involves the administration of **Dazodalibep**, an experimental medication formulated as a **solution for infusion**. Dazodalibep is a biological product developed by Horizon Therapeutics Ireland DAC. The active substance, dazodalibep, is a protein-based compound, specifically an anti-CD40 ligand-Tn3 fusion protein. The medication is administered intravenously, with a maximum daily dose of 63 mg and a total maximum dose of 19,500 mg over a treatment period of up to 309 days. The dosing schedule and participant compliance are monitored throughout the study to ensure adherence to the protocol.
The study also includes a **placebo** control, which is a sterile liquid intended for intravenous infusion following dilution in normal saline. The placebo is aseptically filled into 6R glass vials, each with a nominal volume of 5.0 mL, and 20R glass vials, each with a nominal volume of 15.0 mL. These vials are stoppered with a Flurotec-coated elastomeric stopper and sealed with an aluminum overseal. The placebo is used to maintain the double-blind nature of the study, ensuring that neither the participants nor the investigators know which treatment is being administered, thereby reducing bias in the evaluation of the efficacy and safety of Dazodalibep in participants with Sjögren’s Syndrome with moderate-to-severe systemic disease activity.
Efficacy
The efficacy of **Dazodalibep** in the treatment of Sjögren’s Syndrome with moderate-to-severe systemic disease activity will be assessed through a series of predefined endpoints. The primary endpoint is the change from baseline in the European League Against Rheumatism Sjögren's Syndrome Disease Activity Index (ESSDAI) score at Week 48. Secondary endpoints include the proportion of participants achieving an ESSDAI response, defined as a decrease of at least 5 points from baseline at Week 48, and changes from baseline in various other measures such as the Disease Activity Score in Primary Sjögren's Syndrome Index (DASPRI) dryness domain score, EULAR SS Patient Reported Index (ESSPRI) dryness domain score, tender and swollen joint counts, and PROMIS-Fatigue SF-10a, all at Week 48. Additional secondary endpoints include changes in ESSDAI scores at Weeks 12 and 24, DASPRI total score, ESSPRI total score, and total stimulated salivary flow at Week 48, as well as plasma concentration of Dazodalibep and incidence of treatment-emergent adverse events.
These efficacy parameters will be measured and collected at specified timepoints throughout the trial, utilizing validated scales and patient-reported outcomes. The analysis will focus on comparing the changes from baseline to the specified timepoints, particularly at Week 48, to determine the therapeutic impact of Dazodalibep. The trial is designed to ensure rigorous assessment of efficacy through these comprehensive and clinically relevant endpoints.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Adults ≥ 18 years at time of informed consent (the minimum age for adult participants may be greater than 18 years of age in accordance with country-specific age definitions for adulthood). Participants must be capable of providing their own informed consent (as described in Section 10.6.3, Appendix 6).
- Written informed consent and any locally required authorization (eg, Health Insurance Portability and Accountability Act in the United States, European Union [EU] Data Privacy Directive in the EU) obtained from the participant prior to performing any protocol-related procedures, including screening evaluations . Participants must be able to selfcomplete PatientReported Outcomes (PROs) without assistance.
- Diagnosed with SS by meeting the 2016 American College of Rheumatology (ACR)/EULAR Classification Criteria (Section 10.1, Appendix 1). If SS diagnosis is based on positive anti-Ro autoantibody, anti-Ro positivity must be confirmed by central lab.
- Have an ESSDAI score of ≥ 5 at screening despite current or prior symptomatic or local therapy . The following domains will be scored, but they will not contribute to the minimum ESSDAI score of 5 required for inclusion as these domains may have lower sensitivity to change over duration of study: peripheral nervous system, central nervous system, and pulmonary.
- Positive for either anti-Ro autoantibodies or rheumatoid factor (RF), or both at screening (as per the central laboratory test).
- Females of childbearing potential who are sexually active with a nonsterilized male partner must use a highly effective method of contraception from signing the informed consent form (ICF) must agree to continue using such precautions through the end of the study or 3 months after last IP administration (if participant withdraws from study). Cessation of contraception after this point should be discussed with a responsible physician. The Investigator should evaluate the potential for contraceptive method failure (eg, noncompliance, recently initiated) in relationship to the first dose of IP. A woman of childbearing potential must have a negative highly sensitive serum pregnancy test at screening and must have a negative urine pregnancy test on the day of dosing prior to each dose of IP (see Section 8.3.5). Additional requirements for pregnancy testing during and after study intervention are in Section 8.3.5. The Investigator is responsible for reviewing the participant’s medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy. Highly effective methods of contraception (with a failure rate of < 1% per year when used consistently and correctly) include: • Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: Oral Intravaginal Transdermal Injectable • Progestogen-only hormonal contraception associated with inhibition of ovulation: Oral Injectable Implantable • Intrauterine device • Intrauterine hormone-releasing system • Bilateral tubal occlusion • Azoospermic partner (vasectomized or due to a medical cause) Azoospermia is a highly effective contraceptive method provided that the partner is the sole sexual partner of the woman of childbearing potential and the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should be used. Spermatogenesis cycle is approximately 90 days. Note: documentation of azoospermia for a male participant can come from the site personnel’s review of the participant’s medical records, medical examination, or medical history interview. • Sexual abstinence Sexual abstinence is considered a highly effective method only if it is the preferred and usual lifestyle of the participant and the participant agrees to refrain from heterosexual intercourse from screening through the end of the study follow-up. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. A recommendation that the female partners (of childbearing potential) of male study participants should use a highly effective method of contraception other than a barrier method should be made. - Females of childbearing potential are defined as those who are not surgically sterile (surgical sterilization includes bilateral tubal ligation, bilateral oophorectomy, or hysterectomy) or those who are not postmenopausal (defined as 12 consecutive months with no menses without an alternative medical cause). - Vasectomized partner is a highly effective birth control method provided that the partner is the sole sexual partner of the woman of childbearing potential study participant and that the vasectomized partner has received medical assessment of the surgical success.
- Nonsterilized male participants who are sexually active with a female partner of childbearing potential must use a condom with spermicide (unless spermicide is not available or restricted per local regulations) and refrain from donating fresh unwashed semen from Day 1 through the end of the study or 3 months after the last dose of IP (if participant withdraws from study). His female partner should also be advised of the benefit to use a highly effective method of contraception, as a condom may break or leak. Note: Contraceptive use by men and women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
- 8.Vaccinated against severe acute respiratory syndrome coronavirus 2 (SARSCoV2) according to current local authority guidelines, if any, at least 4 weeks prior to randomization unless the participant refuses vaccination. Initial or subsequent coronavirus disease 2019 (COVID19) vaccine administration is permitted during the study as long as it is not administered during the screening period or within a week after Dose 1; if vaccine is to be administered during this window, screening should be delayed to complete vaccination.
- Meets all of the following tuberculosis (TB) criteria: a. No history of latent or active TB prior to screening, except for latent TB with documented completion of locally appropriate treatment. b. No signs or symptoms suggestive of active TB from medical history or physical examination. c. No recent (≤ 12 weeks of screening) close contact with a person with active TB (close contact is defined as ≥ 4 hours/week OR living in the same household OR in a house where a person with active TB is a frequent visitor). d. Negative interferon gamma release assay (IGRA) test result for TB at screening unless previously treated as per inclusion criterion 9(a). Subjects with an indeterminate test result can repeat the test, but if the repeat test is also indeterminate, they are excluded. If IGRA result by central laboratory is incongruent with recent local testing within 4 weeks prior to or during screening, a repeat assessment will be permitted. e. A chest radiograph (obtained during the screening period or any time within 12 weeks prior to screening) with no evidence of current active TB or other infection, or prior TB, malignancy, or clinically significant abnormalities suggesting an active process (unless due to SS).
Exclusion Criteria
- Individuals with medical history of confirmed deep venous thrombosis, pulmonary embolism, or arterial thromboembolism within 2 years of screening.
- Individuals with: . Any opportunistic infection in the last 12 months (see Section 10.3, Appendix 3), with the exception of a single episode of herpes zoster, non-invasive herpes simplex at any site, oral candidiasis, vaginal candidiasis, or cutaneous fungal infections, which are permitted within the prior 12 months unless of unusual severity. b. Active infections requiring systemic treatment at the time of screening or through randomization, or history of more than 2 infections requiring IV antibiotics within 12 months prior to screening.
- Individuals who have received a live (attenuated) vaccine within the 4 weeks prior to randomization or plan to receive a live vaccine during their participation in the study. Non-live vaccines are permitted during the study (see inclusion criterion 8 in Section 5.1 for COVID-19 vaccines); however, for subjects who plan to receive a vaccine within a month after Dose 1, completing vaccination prior to starting dosing should be considered by the Investigator.
- Last administration of experimental or investigational biologic or oral agents (other than those listed in exclusion criterion 16) < 6 months prior to screening.
- Individuals who have had previous treatment with any biologic B-cell-depleting therapy (eg, rituximab, ocrelizumab, inebilizumab, ofatumumab, or ianalumab) within 12 months or other B-cell-targeting therapy (eg, belimumab) < 3 months prior to screening.
- Use of the following medications: a. Antimalarials (eg, chloroquine, hydroxychloroquine, quinacrine) if they have been initiated or if the dose has changed within 8 weeks prior to screening. b. Methotrexate (MTX) if the dose is > 25 mg/week or if there is any change or initiation of a new dose within 4 weeks prior to screening. c. Azathioprine if the dose is > 150 mg/day or if there is any change in dose or initiation of new dose within 4 weeks prior to screening. d. Leflunomide if the dose is > 20 mg/day or if there is any change or initiation of new dose within 4 weeks prior to screening. e. Mycophenolate mofetil (MMF) if the dose is > 2 g/day or if there is any change to or initiation of a new dose within 4 weeks prior to screening. f. Any other disease-modifying antirheumatic drug (DMARD), immunosuppressant, immunosuppressive biologics, or antiproliferative agents if the last dose was taken within: 4 weeks prior to screening; OR Drug-specific 5 half-lives elimination period (if longer than 4 weeks). g. Any medication that, in the opinion of the Investigator, would interfere with evaluation of the IP or interpretation of participant safety or study results. h. Any increase or initiation of new doses of cevimeline or pilocarpine, or cyclosporine eye drops (Restasis®), lifitegrast (Xiidra®), or any other topical (ophthalmic) anti inflammatory/immunomodulatory eyedrops within 2 weeks prior to screening. i. Use of herbal or homeopathic remedies for underlying rheumatological conditions, specifically sinomenine, tripterygium glycosides, or total glucosides of peony, within 4 weeks prior to screening. j. If being taken, adjustments to the above medications and are not permitted during the screening period (including PRN dosing), and medications are expected to remain stable for the entire study duration.
- Individuals who have received previous treatment with anti-CD40L compounds at any time before screening.
- Individuals with blood tests, at screening, of any of the following: • Aspartate aminotransferase (AST) > 2 × upper limit of normal (ULN) • Alanine aminotransferase (ALT) > 2 × ULN • Total bilirubin (TBL) > 2 × ULN, unless Gilbert’s syndrome is documented in the medical history • Hemoglobin < 90 g/L • Neutrophils < 1.0 × 109 /L • Lymphocytes < 0.5 × 109 /L • Platelets < 100 × 109 /L • International normalized ratio (for prothrombin time INR) > 1.3 × ULN
- History or presence of concomitant polymyositis or dermatomyositis or systemic sclerosis.
- Active malignancy or history of malignancy within the last 5 years, except as follows: a. In situ carcinoma of the cervix treated with apparent success with curative therapy > 12 months prior to screening; OR b. Cutaneous basal cell carcinoma following presumed curative therapy.
- Individuals who are pregnant or lactating or planning to become pregnant or donate eggs during the study or for 3 months after the last dose of IP (if participant withdraws from study) during the study.
- Individuals with known history of severe allergy or reaction to any component of the IP formulation or to any other biologic therapy.
- Individuals with any severe or life-threatening cardiovascular (including vasculitis), respiratory, endocrine, gastrointestinal, hematological, neurological, psychiatric, or systemic disorder or any other condition that, in the opinion of the Investigator, would place the individual at unacceptable risk of complications, interfere with evaluation of the IP, or confound the interpretation of participant safety or study results.
- Individuals who, in the opinion of the Investigator, are unable or unwilling to comply with protocol requirements (eg, active drug or alcohol abuse or for other reasons), including the completion of the Diary for Assessing Sjogren’s Patient-Reported Index (DASPRI) diary and PRO.
- Individuals who have a positive test for hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection. A positive test for hepatitis B at screening is defined as: (1) positive for hepatitis B surface antigen (HBsAg) OR (2) positive for either hepatitis B core antibody (HBcAb), or hepatitis B surface antibody (HBsAb) AND hepatitis B virus (HBV) DNA deteced above the . the lower limit of quantification (LLOQ) by reflex testing by the central laboratory at screening. Individuals with a positive test for or a history of treatment for hepatitis C are excluded unless they have a documented sustained viral response to antiviral drugs approved for the treatment of hepatitis C, defined as an undetectable viral level of hepatitis C RNA at least 24 weeks following completion of therapy. Individuals with advanced fibrosis or cirrhosis due to hepatitis C should not be enrolled.
- Individuals with a positive test for SARS-CoV-2 on the day of randomization. Only those with symptoms suggestive of SARS-CoV-2 at randomization or significant exposure to COVID-19 within 10 days prior to randomization, should be tested. Individuals with COVID-19 or COVID-19 exposure can delay randomization for 10 days and randomize once recovered; otherwise, they will need to rescreen.
- Injectable corticosteroids (including intra-articular [IA] or intramuscular [IM]) or treatment with > 10 mg/day dose of oral prednisone or equivalent within 6 weeks prior to randomization. Concomitant treatment with oral corticosteroids ≤ 10 mg/day prednisone or equivalent for underlying SS, RA, or SLE is permitted provided that the dose is stable for ≥ 2 weeks prior to screening through randomization (Day 1) and is expected to remain stable for the duration of the treatment period. Pro re nata (PRN) use of oral corticosteroids is not allowed during the screening window and through randomization. Inhaled, intranasal, or topical corticosteroids are allowed provided doses are expected to be stable during the study.
- Individuals treated with systemic corticosteroids for indications other than SS, RA, and SLE for more than a total of 2 weeks within 6 months prior to screening.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 04 Mar 2024 | 3 |
 Croatia | Not Recruiting | 04 Mar 2024 | 14 |
 Denmark | Not Recruiting | 04 Mar 2024 | 5 |
 France | Not Recruiting | 04 Mar 2024 | 15 |
 Germany | Not Recruiting | 04 Mar 2024 | 13 |
 Greece | Not Recruiting | 04 Mar 2024 | 10 |
 Hungary | Not Recruiting | 04 Mar 2024 | 10 |
 Italy | Not Recruiting | 04 Mar 2024 | 29 |
 Poland | Not Recruiting | 04 Mar 2024 | 94 |
 Portugal | Not Recruiting | 04 Mar 2024 | 4 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Dazodalibep | Test | SOLUTION FOR INFUSION | SOLUTION FOR INFUSION | 9999 | 99999 | PRD10299897 |
The placebo is formulated as sterile liquid intended for intravenous infusion following dilution in normal saline. The placebo is aseptically filled into 6R glass vials( the nominal volume in each vial is 5.0 mL) and 20R glass vials (the nominal volume in each vial is 15.0 mL) , stoppered with a Flurotec-coated elastomeric stopper, and sealed with an aluminum overseal. | Placebo | N/A | — | — | — | N/A |