| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Discoid Lupus Erythematosus |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 25.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10013072 |
| E.1.2 | Term | Discoid lupus erythematosus |
| E.1.2 | System Organ Class | 10040785 - Skin and subcutaneous tissue disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Primary Efficacy:
To evaluate the effect of daxdilimab compared with placebo in reducing active disease activity at Week 24 in participants with primary DLE. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary Efficacy:
- To evaluate the effect of daxdilimab compared with placebo in reducing DLE disease activity at Week 24 in participants with primary DLE.
- To evaluate the effect of daxdilimab compared with placebo in disease activity and damage in participants with primary DLE.
Pharmacokinetics and Immunogenicity:
To characterize the PK and immunogenicity of daxdilimab in participants with primary DLE.
Safety:
To evaluate the safety and tolerability of daxdilimab in participants with primary DLE.
Exploratory:
To evaluate the effect of daxdilimab compared with placebo on other measures of DLE disease activity.
Pharmacodynamics:
- To characterize the PD of daxdilimab.
- To explore potential associations of genetic variations, gene expression, and profiles of cells and proteins in circulation and tissue with daxdilimab.
Quality of Life:
To evaluate the effect of daxdilimab on the participant’s perceived burden and impact of DLE. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Eligible participants must meet/provide all of the following criteria:
1. Written informed consent and any locally required authorization obtained from the participant/legal representative prior to performing any protocol-related procedures, including screening evaluations.
2. Willing and able to comply with the prescribed treatment protocol and evaluations for the duration of the trial.
3. Adult men or women ≥ 18 and ≤ 75 years of age
4. A diagnosis of DLE for ≥ 6 months prior to screening supported by a history of:
a. A biopsy or
b. a clinical feature score of ≥ 7 on the DLE Classification Criteria (DLECC) scale if a biopsy is not available.
5. Currently active discoid lupus with all the following:
a. Digital photography adjudicated with central reading to confirm a currently active discoid disease lesion.
b. CLASI-A score ≥ 8 related to discoid lesions at Baseline
6. Treatment refractory DLE defined as active disease despite current or historical treatment with a systemic treatment including, but not limited to: antimalarial, methotrexate, mycophenolate, azathioprine, dapsone, corticosteroid, thalidomide, or lenalidomide, OR documented history of intolerance to antimalarials and/or immunosuppressive medications.
7. Participants with active disease who currently are on any of the following therapies must have been on a stable dosage prior to Screening and must remain on a stable dosage through Randomization and for the entire trial as described below:
-Antimalarials must be at a stable dosage for at least 8 weeks prior to Screening and through Randomization.
-Methotrexate ≤ 20 mg/week (oral or SC) at stable dosage and route of administration for at least 4 weeks prior to Screening and through Randomization.
-Mycophenolate mofetil ≤ 2 g/day or mycophenolic acid ≤ 1.44 g/day at stable dosage for at least 4 weeks prior to Screening and through Randomization.
-Azathioprine must be stable for at least 4 weeks prior to Screening and through Randomization.
-Corticosteroid equivalent to prednisone ≤ 10 mg/day at stable dosage for at least 4 weeks prior to Screening and through Randomization.
-Topical corticosteroids and calcineurin inhibitors at stable dosage for at least 1 week prior to Screening and through Randomization.
8. Vaccination status should be up to date per local standards.
9. Females are eligible to participate if they are not pregnant or breastfeeding, and one of the following conditions applies:
-Is a woman of non-childbearing potential (WONCBP) OR - Is a woman of childbearing potential (WOCBP) and using a contraceptive method that is highly effective (ie, has a failure rate of < 1%) , during the study intervention period and for at least 6 months after the last dose of IP and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period. A WOCBP must:
-have a negative serum pregnancy test at Screening and a negative urine pregnancy test at Day 1.
-Additional requirements for pregnancy testing during and after study intervention are located in Section 8.3.5 Pregnancy Testing of study protocol.
-The Investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy. The Investigator should also evaluate the potential for contraceptive method failure (eg, noncompliance, recently initiated) in relationship to the first dose of IP
10. Males are eligible to participate if they agree to the following during the study intervention period and for at least 3 months after the last dose of IP:
-Refrain from donating fresh unwashed semen, PLUS either:
-Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agree to remain abstinent, OR
-Must agree to use contraception/barrier: Agree to use a male condom and should also be advised of the benefit for a female partner to use a highly effective method of contraception as a condom may break or leak when having sexual intercourse with a WOCBP who is not currently pregnant. Effective methods of contraception are listed in Appendix 1 of study protocol.
|
|
| E.4 | Principal exclusion criteria |
Participants will be ineligible for this trial if they meet any of the following criteria:
1. Individuals involved in the conduct of the trial, their employees, or immediate family members
2. Participation in another clinical trial with an investigational IP within 4wks prior to Randomization or within 5published half-lives, whichever is longer
3. Any condition that, in the opinion of the Investigator, would interfere with evaluation of the IP or interpretation of participant safety or trial results.
4. Weight >160kg at Screening
5. History of allergy, hypersensitivity reaction, or anaphylaxis to any component of the IP or to a previous mAb or human Ig therapy
6. Breastfeeding/pregnant women/women who intend to become pregnant anytime from signing the ICF through 6months after receiving the last dose of IP
7. History of drug or alcohol abuse that, in the opinion of the Investigator, might affect participant safety or compliance with visits, or interfere with other trial assessments
8. Major surgery within 8wks prior to Screening or elective surgery planned from Screening through W48
9. Splenectomy
10. Spontaneous or induced abortion, still or live birth, or pregnancy≤ 4wks prior to Screening through Randomization
11. History of clinically significant cardiac disease including unstable angina, myocardial infarction, congestive heart failure within 6months prior to Randomization; arrhythmia requiring active therapy, except for clinically insignificant extra systoles, or minor conduction abnormalities; or presence of clinically significant abnormality on ECG
12. History of cancer within the past 5 years years, except as follows: In situ carcinoma of the cervix treated with apparent success with curative therapy>12months prior to Screening, or Cutaneous basal cell or squamous cell carcinoma treated with curative therapy.
13. Any underlying condition that in the opinion of the Investigator significantly predisposes the participant to infection
14. Participant who has given>499 ml of blood or plasma within 56 days of Screening (during a clinical trial or at a blood bank donation) or plans to give blood or plasma during their participation in the trial or up to
6months after the last IP administration, whichever is longer.
15. Transfusion with blood, packed red blood cells, platelets or treatment with plasmapheresis, or plasma exchange within 8wks prior to Randomization and for the total duration of the trial participation.
16. Known history of a primary immunodeficiency or an underlying condition, e.g.HIV infection, or a positive result for HIV infection.
17. At Screening, any of the following per central laboratory tests:
-Aspartate aminotransferase>2.5×upper limit of normal (ULN)
-Alanine aminotransferase>2.5×ULN
-Total bilirubin>1.5×ULN(unless due to Gilbert’s syndrome)
-Neutrophil count<1500/μL (or<1.5×109/L)
-Platelet count <135,000/μL (or<135×109/L)
-Hemoglobin<10g/dL(or<100g/L)
-Total lymphocyte count <800/μL(or<0.8×109/L)
-Antinuclear antibody titer>1:320
18. All participants will undergo testing for hepatitis B surface antigen
(HBsAg) and hepatitis B core antibody (HBcAb) during Screening.
19. All participants will undergo testing for hepatitis C antibody (HCVAb)
during Screening.
20. Active TB, or a positive IFNγ release assay (IGRA) test at Screening, unless documented history of appropriate treatment for active or latent TB.
21. Any severe herpes virus family infection (including Epstein-Barr virus, cytomegalovirus [CMV]) at any time prior to Randomization, including, but not limited to, disseminated herpes, herpes encephalitis, recent recurrent herpes zoster (defined as 2episodes within the last 2years), or ophthalmic herpes.
22. Any herpes zoster, CMV, or Epstein-Barr virus infection that was not completely resolved 12wks prior to Randomization.
23. Any of the following within 30days prior to signing the ICF and through Randomization:
-Clinically significant active infection in the opinion of the Investigator, including ongoing, and chronic infection requiring antibiotics or antiviral medication (chronic nail infections are allowed).
-Any infection requiring hospitalization or treatment with intravenous anti-infectives.
-A participant with a documented positive SARS-CoV-2 test may be rescreened at least 2wks after a positive test if the participant is asymptomatic and at least 3 wks after symptomatic COVID-19 illness.
24. Opportunbiaistic infection requiring hospitalization or parenteral antimicrol treatment within 2yrs prior to Randomization.
25. Any acute illness or evidence of clinically significant active infection on Day1.
26. Participants who have COVID-19 or other significant infection, or in the judgment of the Investigator, may be at a high risk of COVID-19 or its complications should not be randomized.
NOTE: Other protocol defined Exclusion criteria may apply. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Efficacy:
Mean change in CLASI-A score from Baseline (Day 1) to Week 24 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Baseline (Day 1), W4, W8, W12, W16, W20, W24 |
|
| E.5.2 | Secondary end point(s) |
Secondary Efficacy:
- Proportion of participants who achieve 0 or 1 on the CLA-IGA scale at Week 24 (5-point Likert scale [0-4])
- Proportion of participants who achieve a ≥ 50% reduction in CLASI-A score from Baseline (Day 1) at Week 24
- To evaluate the effect of daxdilimab compared with placebo in disease activity and damage in participants with primary DLE.
- Mean change in the SADDLE from Baseline (Day 1) to Week 24
Pharmacokinetics and Immunogenicity:
- Serum concentration of daxdilimab over time
- Incidence of ADA directed against daxdilimab over time
Safety:
- Incidence of TEAEs
- Incidence of TESAEs
- Incidence of TEAESIs: hypersensitivity reaction, including anaphylaxis, herpes zoster infection, serious (Grade 3 or higher) viral infection/reactivation, opportunistic infection, and malignancy (except non-melanoma skin cancer)
Exploratory:
- Proportion of participants who achieve a ≥ 2-point decrease on the CLA-IGA scale (5-point Likert scale [0-4]) from Baseline (Day 1) over time
- Proportion of participants who achieve 0 or 1 on the CLA-IGA score over time
- Change in CLA-IGA score from Baseline (Day 1) over time
- Change in individual CLASI-A components from Baseline (Day 1) over time
- Mean change in CLASI-D score from Baseline (Day 1) over time
- Change in target discoid lesion characteristics (eg, size, dyspigmentation, etc) assessed by digital photography from Baseline over time
- Proportion of participants with onset of one or more new discoid lesions (assessed by digital photography) over time
- Assessment by digital photography of whether there is hair regrowth within lesions over time
- Mean change in the DLECC scale from Baseline (Day 1) to Week 24 and Week 48
Pharmacodynamics:
- Change in the following PD biomarkers from Baseline (Day 1) over time: pDCs (in tissue and blood), IFNα, MxA, and IFN gene signature (in blood)
- To explore potential associations of genetic variations, gene expression, and profiles of cells and proteins in circulation and tissue with daxdilimab.
- Change in the following exploratory biomarkers over time: cell numbers, cytokines, chemokines, and gene expression
Quality of Life:
- change in quality of life endpoints from Baseline (Day 1) over time: PGA, CLE-QoL, DLQI, and EQ-5D-DL.
- PGIC from Week 4 over time |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Baseline (Day 1), W4, W8, W12, W16, W20, W24, W28, W32, W36, W40, W44, W48, W52, W56 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 45 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Brazil |
| Canada |
| Israel |
| United States |
| Bulgaria |
| Czechia |
| Denmark |
| France |
| Germany |
| Greece |
| Poland |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of trial is defined as the date of the last visit of the last participant in the trial or last scheduled procedure (Week 56) for the last participant in the trial globally. A participant is considered to have completed the trial if the participant has completed all periods of the trial including the last visit or the last scheduled procedure (Week 56). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 17 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 3 |
Print
