| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Primary Sjögren’s syndrome (pSS) |
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| E.1.1.1 | Medical condition in easily understood language |
| Primary Sjögren’s syndrome (pSS) |
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| E.1.1.2 | Therapeutic area | Body processes [G] - Immune system processes [G12] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10040767 |
| E.1.2 | Term | Sjogren's syndrome |
| E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
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| 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 |
| To evaluate the efficacy of each active treatment combination (hydroxychloroquine + leflunomide and hydroxychloroquine + mycophenolate mofetil) based on proportion of responder patients according to preliminary STAR at week 24. |
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| E.2.2 | Secondary objectives of the trial |
Cohort 1 and 2 together: To evaluate efficacy of each active treatment combination based on proportion of responder patients according to preliminary STAR at w24
Cohorts 1 and 2 separately: To evaluate efficacy of each active treatment combination at w12 and 36 based on proportion of responder patients according to preliminary STAR
To evaluate efficacy of each active treatment combination at w12, 24 and 36 based on change in ESSPRI.
To evaluate efficacy of each active treatment combination at w12, 24 and 36 based on change in ESSDAI/clinESSDAI
To assess discriminant capacity of STAR (preliminary STAR and alter opt) relative to ESSDAI (clinESSDAI)/ESSPRI to detect changes at w24 and 36
To evaluate effect of each active treatment combination on - glandular function at w12, 24, 36
- anxiety and depression, health-related QoL at w12, 24 and 36
To evaluate utility of the PEPSS WebApp in collecting symptoms on a daily basis over 24 weeks |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Cohorts 1 and 2 separately:
• To evaluate the efficacy of each active treatment combination at week 12, 24 and 36 based on proportion of responder patients according to STAR alternate options 1,2,3,4,5,7, 8, 9, 10, 12, 13, 14, 15, 16 and 17.
• To evaluate the efficacy of each active treatment combination at week 12, 24 and 36 based on change in STAR alternate options 11, 18 and 19.
• To evaluate the efficacy of each active treatment combination at week 12, 24 and 36 based on change in PhGA, PatGA and oral dryness VAS and ocular dryness VAS.
• To evaluate the efficacy of each active treatment combination at week 24 and 36 based on change in SSSD.
• To evaluate the effect of each active treatment combination based on patient’s opinion and physician evaluation of change.
• To evaluate the effect of each active treatment combination on sexual quality of life and ocular surface disease index at week 12, 24 and 36.
• To assess and compare the discriminant capacity of meibography and non-invasive tear break-up time techniques to detect changes.
• To assess the discriminant capacity of the novel ultrasound scoring system to detect changes.
• To assess the utility of the biosensors to assess fatigue and detect changes.
• To evaluate the change of several biomarkers from baseline after treatment.
• To evaluate if the baseline level of several biomarkers is predictive of the treatment response.
• To evaluate the change of salivary gland histologic abnormalities after treatment. |
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| E.3 | Principal inclusion criteria |
Cohort 1
- Having given written informed consent prior to undertaking any study-related procedures.
- Patients with pSS according to ACR/EULAR 2016 criteria or AECG 2002 criteria (see addenda 4)
- With a high level of symptoms (ESSPRI ≥ 5) and low systemic disease activity (ESSDAI < 5).
- Negative pregnancy test (serum at screening)
- Use highly reliable contraception (as defined in section 6.3) during research treatment from the screening and for two years after stopping treatment.
Cohort 2
- Having given written informed consent prior to undertaking any study-related procedures.
- Patients with pSS according to ACR/EULAR 2016 criteria or AECG 2002 criteria (see addenda 4)
- With moderate/high systemic disease activity, as defined by ESSDAI ≥ 5.
- Negative pregnancy test (serum at screening)
- Use highly reliable contraception (as defined in section 6.3) during research treatment from the screening and for two years after stopping treatment.
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| E.4 | Principal exclusion criteria |
For both cohorts:
- Age < 18 years
- Pregnant or breastfeeding women or women wanted to conceive either during or within two years after the end of the treatment period
- Women of childbearing potential not using highly effective methods of contraception (as defined in section 6.3)
- Participation in another interventional trial
- Contra-indication to HCQ: pre-existing retinopathy, hypersensitivity to HCQ or to any of the excipients of the specialty used
- Contra-indication to MMF: hypersensitivity to mycophenolate mofetil, acid mycophenolic, mycophenolate sodium or to any of the excipients of the specialty used
- Contra-indication tor LEF: hypersensitivity to the active substance, the main active metabolite teriflunomide or to any excipients of the specialty used.
- Concomitant treatment with corticosteroids more than 10 mg/day of prednisone equivalent at screening or inclusion (randomisation)
- Concomitant treatment with other immunomodulators including methotrexate, azathioprine, cyclophosphamide, cyclosporine and tacrolimus
- Previous treatment with HCQ, LEF, MMF in the last 3 months
- Previous treatment with rituximab, other B-cell targeted biologic therapy or cyclophosphamide in the last 6 months
- Previous treatment with anti-TNF, abatacept, tocilizumab or belimumab or any other biologic in the setting of a past clinical trial in the last 3 months
- Severe life-threatening systemic involvement requiring cyclophosphamide or high dose corticosteroids, or any drug considered as an exclusion criteria
- Impairment of other severe immunodeficiency states
- Patients with active malignancy or history of malignancy within the last 5 years except non-melanoma skin cancer
- Patients with history of gastrointestinal tract ulceration, hemorrhage and perforation
- Patients with history of cardiomyopathy
- Patients with known hereditary deficiency of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) such as Lesch-Nyhan and Kelley-Seegmiller syndrome
- Serious infection in the past month
- Evidence of active tuberculosis infection
- Active HCV (positive PCR)
- Active HBV infection (positivity for HBS antigen, or positivity for anti-HBC antibody without any HBS antigen)
- HIV infection (positive serology)
- Positive SARS-Cov2 PCR (if vaccinated for COVID-19, no PCR is required; if history of COVID-19 infection, positive serology is sufficient)
- Cytopenia defined as neutrophils < 1.0 G/L, lymphocytes < 0.5 G/L, Hb < 10 g/dl or platelets < 100 G/L
- Moderate to severe renal insufficiency (GFR < 30 ml/min)
- Severe hypogammaglobulinemia defined as gamma globulins or IgG < 5 g/l
- Reduced hepatic function: AST or ALT > 2x ULN (re-testing is allowed, see section 5.10)
- Prolonged ECG's corrected QT interval (>500 ms)
- Known history of maculopathy
- Patients will be informed of the risk of alcohol consumption and will be recommended to avoid alcohol during the entire study
- Not affiliated to a social security regime (specific for France) |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Each cohort is analysed separately
• Cohort 1: Proportion of patients achieving a response according to preliminary STAR at week 24 between each active treatment arm and placebo arm.
• Cohort 2: Proportion of patients achieving a response according to preliminary STAR at week 24 between each active treatment arm and placebo arm.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Cohorts 1 and 2 together
• Cohort 1 and 2: Proportion of patients achieving a response according to preliminary STAR at week 24 between each active treatment arm and placebo arm.
Cohorts 1 and 2 (the two cohorts will be analysed separately):
• Proportion of patients achieving a response according to preliminary STAR from baseline at week 12 and 36 between each active treatment arm and placebo arm.
• Change in ESSPRI from baseline at week 12, 24 and 36 between each active treatment arm and placebo arm. The difference of ESSPRI score at week 12, 24 and 36 (adjusted for baseline value) will be also compared between each active treatment arm and placebo arm.
• Proportion of patients achieving a response in ESSPRI (defined as a decrease of ESSPRI score of ≥ 1 (or ≥ 15%)) from baseline at week 12, 24 and 36 between each active treatment arm and placebo arm.
• Change in ESSDAI/clinESSDAI from baseline at week 12, 24 and 36 between each active treatment arm and placebo arm. The difference of ESSDAI/clinESSDAI score at week 12, 24 and 36 (adjusted for baseline value) will be also compared between each active treatment arm and placebo arm.
Cohort 1: This analysis will be performed only if the number of patients with ESSDAI/clinESSDAI > 0 is sufficient.
• Proportion of patients achieving a response in ESSDAI/clinESSDAI (defined as improvement of ESSDAI/clinESSDAI ≥ 3 points) from baseline at week 12, 24 and 36 between each active treatment arm and placebo arm.
• Discriminant capacity of STAR (preliminary STAR and alternate options) relative to ESSDAI (clinESSDAI)/ESSPRI at week 24 and 36 to detect changes in the placebo arm versus in each active treatment arm in each cohort and globally
• Change in unstimulated whole salivary flow from baseline at week 12, 24 and 36 between each active treatment arm and placebo arm.
• Change in Schirmer’s score from baseline at week 12, 24 and 36 between each active treatment arm and placebo arm.
• Change in Tear Break-up time score from baseline at week 24 and 36 between each active treatment arm and placebo arm.
• Change in Ocular Staining Score from baseline at week 24 and 36 between each active treatment arm and placebo arm.
• Change in score of HADS questionnaire from baseline at week 12, 24 and 36 between each active treatment arm and placebo arm.
• Change in score of EQ-5D-5L questionnaire from baseline at week 12, 24 and 36 between each active treatment arm and placebo arm.
• Change in symptoms collected using the PEPSS WebApp from baseline to week 24 between each active treatment arm and placebo arm. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| 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 | Yes |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
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| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 34 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| 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
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
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