This study has been transitioned to CTIS with ID 2023-510054-16-00 check the CTIS register for the current data. Primary objective:To evaluate the efficacy of each active treatment combination (hydroxychloroquine + leflunomide and hydroxychloroquine…
ID
Source
Brief title
Condition
- Autoimmune disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoints:
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.
Secondary outcome
Secondary endpoints:
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.
Exploratory endpoints:
Cohorts 1 and 2 (the two cohorts will be analysed separately):
* Proportion of patients achieving a response in STAR alternate options 1, 2,
3, 4, 5, 7, 8, 9, 10, 12, 13, 14, 15, 16 and 17 from baseline at week 12, 24
and 36 between each active treatment arm and placebo arm.
* Change in STAR alternate options 6, 11, 18 and 19 from baseline at week 12,
24 and 36 between each active treatment arm and placebo arm. The difference of
STAR score at week 12, 24 and 36 (adjusted for baseline value) will be also
compared between each active treatment arm and placebo arm.
* Validation of the final STAR
* Change in oral dryness and ocular dryness Visual Analog Scale (VAS) from
baseline at week 12, 24 and 36 between each active treatment arm and placebo
arm.
* Change in PhGA from baseline at week 12, 24 and 36 between each active
treatment arm and placebo arm.
* Change in PatGA from baseline at week 12, 24 and 36 between each active
treatment arm and placebo arm.
* Change in SSSD from baseline at week 24 and 36 between each active treatment
arm and placebo arm.
* Proportion of patients considered as improved according to patient opinion
and physician evaluation of change at week 24 and week 36
* Change in meibography measurements from baseline at week 24 between each
active treatment arm and placebo arm.
NECESSITY protocol, version 1-3 of 09 June 2021 10/71
This document is the property of DRCI / AP-HP. All reproduction is strictly
prohibited.
Version date: April 2018
* Change in non-invasive tear break-up time measurements from baseline at week
24 between each active treatment arm and placebo arm.
* Change in the novel ultrasound scoring system (SGUS) from baseline at week 24
between each active treatment arm and placebo arm.
* Change in the measurements collected with the two biosensors as surrogate
measures of fatigue from baseline at week 12 and 24 between each active
treatment arm and placebo arm.
* Change in levels of several biomarkers from baseline at week 24 between each
active treatment arm and placebo arm.
* Change in the salivary gland histologic abnormalities from baseline at week
24 between each active treatment arm and placebo arm.
* Change in score of OSDI questionnaire from baseline at week 24 and 36 between
each active treatment arm and placebo arm.
* Change in score of FSFI questionnaire from baseline at week 24 and 36 between
each active treatment arm and placebo arm.
Background summary
There are no approved treatments for pSS and the clinical endpoints currently
used in clinical trials are inadequate to capture all aspects of the disease
that should be evaluated in clinical trials. The newly developed composite
endpoint: Sjögren*s Tool for Assessing Response to treatment (STAR) will allow
a more specific and meaningful assessment of treatment efficacy in pSS.
Because of the heterogeneity of the disease and of the central role of the
interplay between B- and T-cells in the pathogenesis, it is worth to evaluate
combination of conventional synthetic immunomodulatory drugs targeting both B-
and T-cells.
Study objective
This study has been transitioned to CTIS with ID 2023-510054-16-00 check the CTIS register for the current data.
Primary objective:
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.
Secondary objectives:
Cohort 1 and 2 together:
To evaluate the efficacy of each active treatment combination based on
proportion of responder patients according to preliminary STAR at week 24.
Cohorts 1 and 2 separately:
* To evaluate the efficacy of each active treatment combination at week 12 and
36 based on proportion of responder patients according to preliminary STAR.
To evaluate the efficacy of each active treatment combinations at week 12, 24
and 36 based on change in ESSPRI.
* To evaluate the efficacy of each active treatment combination at week 12, 24
and 36 based on change in ESSDAI/clinESSDAI.
* To assess the discriminant capacity of STAR (preliminary STAR and alternate
options) relative to ESSDAI (clinESSDAI)/ESSPRI to detect changes at week 24
and 36.
* To evaluate the effect of each active treatment combination on glandular
function at week 12, 24, 36.
* To evaluate the effect of each active treatment combination on anxiety and
depression, health-related quality of life at week 12, 24 and 36.
* To evaluate the utility of the PEPSS WebApp in collecting symptoms on a daily
basis over 24 weeks.
Study design
Randomized double-blind controlled trial. Patients are stratified in 2 cohorts
and randomized between 3 arms:
* triple placebo,
* hydroxychloroquine (HCQ) 400mg/d, leflunomide (LEF) 20mg/d and placebo of
mycophenolate mofetil (MMF),
* or hydroxychloroquine 400mg/d, mycophenolate mofetil 2000mg/d and placebo of
leflunomide.
The duration of the treatment will be 24 weeks. Patients will be followed up
until week 36 (12 weeks after the end of treatment period).
Intervention
Investigational medicinal product(s)
- Hydroxychloroquine: Plaquenil* 200 mg tablets
* Mycophenolate Mofetil 500 mg tablets
* Leflunomide 20 mg tablets
Comparator treatment
- Oral placebo tablets for HCQ, LEF and MMF
Interventions added for the trial
* ESSDAI/ClinESSDAI, PhGA, STAR scores, Physician evaluation of change
* Patient questionnaires (ESSPRI, VAS (ocular and oral dryness), PatGA, HADS,
FSFI, EQ-5D-5L, OSDI, SSSD, Patient*s opinion)
* Schirmer*s test, unstimulated whole salivary flow, Tear Break Up Time (TBUT),
Ocular Staining Score (OSS)
* Non-invasive TBUT, meibography (optional)
* PEPSS webapp (optional)
* Biosensors (UK centres only, optional)
* Ultrasound salivary gland (optional)
* Minor salivary gland biopsy (optional)
* Blood collection (serum, RNA)
Study burden and risks
The risk level of the research was estimated as high
Hydroxychloroquine, leflunomide and mycophenolate mofetil are frequently given
off label to patients with pSS. Their safety profile is well known so the risks
for the patient will be minimal.
avenue Claude Vellefaux 1
Paris 75010
FR
avenue Claude Vellefaux 1
Paris 75010
FR
Listed location countries
Age
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.
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)
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 | CTIS2023-510054-16-00 |
| EudraCT | EUCTR2019-002470-32-NL |
| CCMO | NL72086.042.21 |