DAZODALIBEP for Sjogren's syndrome | Sjögren's syndrome with moderate-to-severe systemic disease activity

Inclusion criteria

• {"criterion_text":"- 1. 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)."}
• {"criterion_text":"- 2. 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."}
• {"criterion_text":"- 3. 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."}
• {"criterion_text":"- 4. 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."}
• {"criterion_text":"- 5. Positive for either anti-Ro autoantibodies or rheumatoid factor (RF), or both at screening (as per the central laboratory test)."}
• {"criterion_text":"- 6. 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 female study participant and that the vasectomized partner has received medical assessment of the surgical success."}
• {"criterion_text":"- 7. 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."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- 9. 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

• {"criterion_text":"- 1.\tIndividuals with medical history of confirmed deep venous thrombosis, pulmonary embolism, or arterial thromboembolism within 2 years of screening."}
• {"criterion_text":"- 3.\tActive 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."}
• {"criterion_text":"- 4.\tIndividuals 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."}
• {"criterion_text":"- 5.\tIndividuals with known history of severe allergy or reaction to any component of the IP formulation or to any other biologic therapy."}
• {"criterion_text":"- 6.\tIndividuals 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."}
• {"criterion_text":"- 7.\tIndividuals 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."}
• {"criterion_text":"- 8.\tIndividuals 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."}
• {"criterion_text":"- 9.\tIndividuals 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."}
• {"criterion_text":"- 10.\tIndividuals 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."}
• {"criterion_text":"- 11.\tIndividuals 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."}
• {"criterion_text":"- 12.\tLast administration of experimental or investigational biologic or oral agents (other than those listed in exclusion criterion 16) < 6 months prior to screening."}
• {"criterion_text":"- 13.\tIndividuals 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."}
• {"criterion_text":"- 16.\t 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."}
• {"criterion_text":"- 17.\tIndividuals who have received previous treatment with anti-CD40L compounds at any time before screening."}
• {"criterion_text":"- 18.\tIndividuals 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"}
• {"criterion_text":"- 2.\tHistory or presence of concomitant polymyositis or dermatomyositis or systemic sclerosis."}

Primary endpoints

• {"endpoint_text":"- Change from baseline in ESSDAI score at Week 48","definition_or_measurement_approach":"Change from baseline in ESSDAI (EULAR Sjögren's Syndrome Disease Activity Index) score measured at Week 48 compared to baseline."}

Secondary endpoints

• {"endpoint_text":"- Proportion of participants achieving ESSDAI[5] response, defined as a decrease of at least 5 points from baseline in the ESSDAI at Week 48 without premature discontinuation from treatment and without receiving rescue or potentially confounding therapy (Plan A and Plan B).","definition_or_measurement_approach":"Responder analysis: proportion meeting ≥5-point ESSDAI reduction at Week 48 without premature discontinuation or rescue therapy."}
• {"endpoint_text":"- Change from baseline in DASPRI dryness domain score at Week 48 (Plan A)","definition_or_measurement_approach":"Change from baseline in the DASPRI (Diary for Assessing Sjogren’s Patient-Reported Index) dryness domain at Week 48."}
• {"endpoint_text":"- Change from baseline in EULAR SS Patient Reported Index (ESSPRI) dryness domain score at Week 48 (Plan B)","definition_or_measurement_approach":"Change from baseline in ESSPRI dryness domain at Week 48 (patient-reported index)."}
• {"endpoint_text":"- Change from baseline in tender and swollen joint counts at Week 48 (Plan A and Plan B)","definition_or_measurement_approach":"Change from baseline in number of tender and swollen joints at Week 48."}
• {"endpoint_text":"- Change from baseline in PROMIS-Fatigue SF-10a at Week 48 (Plan A and Plan B)","definition_or_measurement_approach":"Change from baseline in PROMIS-Fatigue short form (SF-10a) score at Week 48."}
• {"endpoint_text":"- Change from baseline in ESSDAI score at Week 12 and Week 24 (Plan A and Plan B)","definition_or_measurement_approach":"Change from baseline in ESSDAI at intermediate timepoints Week 12 and Week 24."}
• {"endpoint_text":"- Change from baseline in DASPRI total score at Week 48 (Plan A)","definition_or_measurement_approach":"Change from baseline in total DASPRI score at Week 48."}
• {"endpoint_text":"- Change from baseline in ESSPRI total score at Week 48 (Plan B)","definition_or_measurement_approach":"Change from baseline in total ESSPRI score at Week 48."}
• {"endpoint_text":"- Change from baseline in total stimulated salivary flow at Week 48 (Plan A and Plan B)","definition_or_measurement_approach":"Change from baseline in stimulated salivary flow (objective salivary flow measurement) at Week 48."}
• {"endpoint_text":"- Plasma concentration of dazodalibep","definition_or_measurement_approach":"Pharmacokinetic plasma concentrations of dazodalibep measured at scheduled timepoints."}
• {"endpoint_text":"- Incidence of treatmentemergent adverse events (TEAEs), treatmentemergent serious adverse events, (TESAEs), and adverse events of special interest (AESIs).","definition_or_measurement_approach":"Safety assessments: counts and incidence of TEAEs, TESAEs and AESIs during treatment and follow-up."}

Methods

• Digital advertising: Paid search and digital ads (country-specific digital ad materials documented, e.g., Germany DAZ-Program digital ads, paid-search; program website and referral confirmation emails exist).
• Printed materials and direct mail: Brochures, brochure-inserts, program flyers and prescreener documents prepared for multiple countries (e.g., Germany, Slovenia, Hungary, Croatia, Poland, France, Italy, Portugal, Spain, Belgium, Greece).
• Healthcare professional outreach: GP/physician letters and site-based referrals (GP letters documented in country kits).
• Clinical site prescreening and site-based recruitment: Site prescreeners and secondary screening packets described.
• Patient advocacy/registry engagement: Sjogren’s Foundation involvement in investigator training and development of patient recruitment materials.
• Vendor-supported recruitment: Third-party recruitment vendors (eg, Continuum Clinical LLC) contracted for patient recruitment and retention planning, study/site support and campaign development.

Primary sponsor

Full Name

Horizon Therapeutics Ireland Designated Activity Company

Organisation Type

Pharmaceutical company

Country Of Registered Address

Ireland

Contract research organisations

Name

PPD Development LP

Responsibilities

Contract Research Organization, Clinical Database Management, Pharmacovigilance services.

Name

PPD Global Ltd.

Responsibilities

Contract Research Organization, Clinical Database Management, Pharmacovigilance services in Greece.

Name

Continuum Clinical LLC

Responsibilities

Patient recruitment and retention planning, study and site support, developing patient recruitment campaigns, and reporting and analytics.

Name

Almac Clinical Services (Ireland) Limited

Responsibilities

IP Management and Depot.

Name

Bioclinica Inc.

Responsibilities

Central ultrasound reader.

Third parties

• {"country":"United States","full_name":"PPD Development LP","duties_or_roles":"Contract Research Organization, Clinical Database Management, Pharmacovigilance services.","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Suvoda LLC","duties_or_roles":"eClinical services (responsibility code listed as '3').","organisation_type":"Non-Pharmaceutical company"}
• {"country":"Switzerland","full_name":"Labcorp Central Laboratory Services S.a.r.l.","duties_or_roles":"Central laboratory services.","organisation_type":"Pharmaceutical company (central laboratory)"}
• {"country":"United States","full_name":"Clinical Ink Inc.","duties_or_roles":"eCOA, ePRO and Patient Diary.","organisation_type":"Pharmaceutical company / eCOA vendor"}
• {"country":"United States","full_name":"Medidata Solutions Inc.","duties_or_roles":"RTSM/clinical data management support.","organisation_type":"Non-Pharmaceutical company (RWS/eClinical vendor)"}
• {"country":"United States","full_name":"Continuum Clinical LLC","duties_or_roles":"Patient recruitment and retention planning, study and site support, developing patient recruitment campaigns, and reporting and analytics.","organisation_type":"Pharmaceutical company / recruitment vendor"}
• {"country":"Ireland","full_name":"Almac Clinical Services (Ireland) Limited","duties_or_roles":"IP Management and Depot.","organisation_type":"Pharmaceutical company / logistics"}
• {"country":"Greece","full_name":"PPD Global Ltd.","duties_or_roles":"Contract Research Organization, Clinical Database Management, Pharmacovigilance services in Greece.","organisation_type":"Pharmaceutical company / CRO affiliate"}
• {"country":"United States","full_name":"Sjogren’s Foundation","duties_or_roles":"Investigator training (ESSDAI assessment training); developing patient recruitment materials (patient letters, physician letters and social media ads).","organisation_type":"Health care / patient advocacy"}
• {"country":"United States","full_name":"Bioclinica Inc.","duties_or_roles":"Central ultrasound reader.","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Unisphere Travel Ltd. Inc.","duties_or_roles":"Travel vendor: make travel arrangements and/or provide reimbursement services for approved patient expenses and stipends (US and UK).","organisation_type":"Non-Pharmaceutical company (travel vendor)"}