A Study to Evaluate the Safety, Tolerability and Efficacy of MHV370 in Participants With Sjogren's Syndrome (SjS) or Mixed Connective Tissue Disease (MCTD)

Study Overview
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Brief Summary
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This study is a basket trial designed to establish safety, tolerability and efficacy of MHV370 in Sjögren's Syndrome (SjS) and Mixed Connective Tissue Disease (MCTD).

Detailed Description
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This is a randomized, participant and investigator blinded, placebo-controlled, multi center parallel group basket study to evaluate the safety, tolerability and efficacy of MHV370 in participants with Sjögren's Syndrome (SjS) or with Mixed Connective Tissue Disease (MCTD). Participants first underwent a screening period of up to 6 weeks, followed by a treatment duration of 24 weeks and a follow-up period of 4 weeks. Total study duration for each participant was up to 34 weeks. Participants with SjS were randomized in a 1:1 ratio to MHV370 or placebo and participants with MCTD were randomized in a 1:1 ratio to MHV370 or placebo.

Official Title
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A Multi-center, Randomized, Participant- and Investigator- Blinded, Placebo-controlled, Parallel Group Basket Study to Evaluate the Safety, Tolerability and Efficacy of MHV370 in Participants With Sjögren's Syndrome or Mixed Connective Tissue Disease

Conditions
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Sjogren Syndrome, Mixed Connective Tissue Disease

Intervention / Treatment
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* Drug: MHV370
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: SjS and MCTD: • Fully vaccinated with any locally approved COVID-19 vaccination including booster vaccinations if required by local guidelines SjS: Unstimulated whole salivary flow rate of > 0 mL/min at screening Classification of Sjögren's Syndrome according to the 2016 ACR/EULAR criteria at screening Screening ESSDAI (based on weighted score) ≥ 5 from 8 defined domains (biologic, hematologic, articular, cutaneous, glandular, lymphadenopathy, renal, constitutional). MCTD: Diagnosis of MCTD based on criteria like a) Raynaud's phenomenon b) At least two of the four following signs: i) synovitis, ii) myositis, iii) swollen fingers and vi) interstitial lung disease Patients with overlap syndromes, i.e. patients meeting diagnostic criteria for systemic autoimmune disease other than MCTD may be included unless they have major organ involvement as judged by the investigator Exclusion Criteria: SjS and MCTD: Prior use of B-cell depleting therapy within 6 months of baseline. For participants who received B-cell depleting therapy within 6 -12 months of baseline visit, B-cell count should be within normal range Prior treatment with any of the following within 3 months of baseline: CTLA4-Fc Ig (abatacept), Anti-TNF mAb, Intravenous Ig, Plasmapheresis, i.v. or oral cyclophosphamide, i.v. or oral cyclosporine A Screening CBC laboratory values as follows: Hemoglobin levels < 8 g/dL (< 5 mmol/L), Total leukocyte count < 2,000/µL (2 x 109/L), Platelets < 50,000/µL (50 x 109/L), Neutrophil count < 1,000/µL (1 x 109/L) Pregnant or nursing (lactating) women Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they use a highly effective method of contraception SjS: Sjögren's Syndrome overlap syndromes where another autoimmune disease constitutes the primary illness Required regular use of medications known to cause, as a major side effect, dry mouth / eyes Other protocol-defined inclusion/exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SjS participants: MHV370<br>SjS participants randomized in the MHV370 arm will be treated with MHV370 for 24 weeks. Double-blind supply will be used. | Drug: MHV370<br>* MHV370 for 24 weeks<br>|
| Placebo Comparator: SjS participants: Placebo<br>SjS participants randomized in the placebo arm will be treated with placebo for 24 weeks. Double-blind supply will be used. | Drug: Placebo<br>* Placebo for 24 weeks<br>|
| Experimental: MCTD participants: MHV370<br>MCTD participants randomized in the MHV370 arm will be treated with MHV370 for 24 weeks. Double-blind supply will be used. | Drug: MHV370<br>* MHV370 for 24 weeks<br>|
| Placebo Comparator: MCTD participants: Placebo<br>MCTD participants randomized in the placebo arm will be treated with placebo for 24 weeks. Double-blind supply will be used. | Drug: Placebo<br>* Placebo for 24 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SjS participants: Change from baseline in Eular Sjögren's Disease Activity Index (ESSDAI) after 24 weeks of treatment | The ESSDAI is an established disease outcome measure for Sjögren's syndrome that classifies disease activity in 3-4 levels according to their severity (i.e., no, low, moderate, high), over each of 12 organ-specific domains. These scores are then summed across the 12 domains in a weighted manner to provide the total score: biologic (1), hematologic (2), articular (2), glandular (2), cutaneous (3), constitutional (3), lymphadenopathy (4), renal (5), pulmonary (5), PNS (5), CNS (5) and muscular (6). The maximum possible score is 123, where a higher ESSDAI score indicates more severe symptoms. A negative change score from baseline indicates improvement. | baseline, week 24 | 
| MCTD participants: Change from baseline in physician's global assessment scale (PhGA) after 24 weeks of treatment | The physician's global assessment scale is used for the Investigator to rate the disease activity of their patient using 100 mm visual analog scale (VAS) ranging from no disease activity (0) to maximal disease activity (100). A negative change score from baseline indicates improvement. | baseline, week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SjS and MCTD participants: Maximum Observed Blood Concentrations (Cmax) of MHV370 at steady state | The maximum (peak) observed blood drug concentration after single dose administration (ng / mL). Pharmacokinetic (PK) parameters will be calculated based on MHV370 blood concentrations determined by a validated liquid chromatography and tandem mass spectrometry (LC-MS/MS) method with a lower limit of quantification of 1 ng/mL. Cmax will be determined using non-compartmental methods. | pre-dose, 0.5, 1, 2 ,4 and 6 hours after dosing at week 4 and predose and 4 hours after dosing at weeks 12 and 24 | 
| SjS and MCTD participants: Area under the blood concentration-time curve from time zero to time of last measurable concentration (AUClast) of MHV370 at steady state | The AUC from time zero to the last measurable concentration sampling time (tlast) (ng x h / mL). Pharmacokinetic (PK) parameters will be calculated based on MHV370 blood concentrations determined by a validated liquid chromatography and tandem mass spectrometry (LC-MS/MS) method with a lower limit of quantification of 1 ng / mL. AUClast will be determined using non-compartmental methods. | pre-dose, 0.5, 1, 2 ,4 and 6 hours after dosing at week 4 and predose and 4 hours after dosing at weeks 12 and 24 | 
| SjS and MCTD participants: Time to Reach Maximum Blood Concentrations (Tmax) of MHV370 at steady state | The time to reach maximum (peak) blood drug concentration after single dose administration (h). Pharmacokinetic (PK) parameters will be calculated based on MHV370 blood concentrations determined by a validated liquid chromatography and tandem mass spectrometry (LC-MS/MS) method with a lower limit of quantification of 1 ng/mL. Tmax will be determined using non-compartmental methods. | pre-dose, 0.5, 1, 2 ,4 and 6 hours after dosing at week 4 and predose and 4 hours after dosing at weeks 12 and 24 | 
| SjS and MCTD participants: Change from baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scale | The FACIT-F v4 is a short, 13-item patient-reported measure, easy-to-administer tool that measures an individual's level of fatigue during their usual daily activities over the past week. The level of fatigue is measured on a 5-point Likert scale (0 = not at all, 1 = a little bit, 2 = somewhat, 3 = quite a bit, 4 = very much). To score the FACIT-fatigue, all items are summed to create a single fatigue score with a range from 0 to 52, where a higher FACIT-F score indicates more severe symptoms. A negative change score from baseline indicates improvement. | baseline, weeks 4, 8, 12, 20 and 24 | 
| SjS and MCTD participants: Change from baseline in Physician Global Assessment (PhGA) | The physician's global assessment scale is used for the Investigator to rate the disease activity of their patient using 100 mm visual analog scale (VAS) ranging from no disease activity (0) to maximal disease activity (100). A negative change score from baseline indicates improvement. | SjS participants: baseline, weeks 4, 8, 12, 20 and 24. MCTD participants: baseline, weeks 4, 8, 12, and 20. | 
| SjS participants: Change from baseline in Eular Sjögren's Syndrome Disease Activity Index (ESSDAI) | The ESSDAI is an established disease outcome measure for Sjögren's syndrome that classifies disease activity in 3-4 levels according to their severity (i.e., no, low, moderate, high), over each of 12 organ-specific domains. These scores are then summed across the 12 domains in a weighted manner to provide the total score: biologic (1), hematologic (2), articular (2), glandular (2), cutaneous (3), constitutional (3), lymphadenopathy (4), renal (5), pulmonary (5), PNS (5), CNS (5) and muscular (6). The maximum possible score is 123, where a higher ESSDAI score indicates more severe symptoms. A negative change score from baseline indicates improvement. | baseline, weeks 4, 8, 12 and 20 | 
| SjS participants: Change from baseline in Eular Sjögren's Syndrome Patient Reported Index (ESSPRI) | The ESSPRI is an established disease outcome measure for Sjögren's syndrome. The ESSPRI is a patient-reported, subjective symptom index which consists of three questions covering the cardinal symptoms of Sjögren's syndrome: dryness, fatigue and pain (articular and/or muscular). The participant can assess severity of symptoms they experience on a single numerical scale of 0-10 (0 =no symptom at all and 10 = worst symptom imaginable) for each of the three domains. The overall ESSPRI score is calculated as the mean of the three individual domains where all domains carry the same weight. Minimum score can be 0 and maximum score can be 10, where a higher ESSPRI score indicates more severe symptoms. A negative change score from baseline indicates improvement. | baseline, weeks 4, 8, 12, 20 and 24 | 
| SjS participants: Change from baseline to the salivary flow rate | Unstimulated whole salivary fluid secretions are collected over 5 minutes from participants. The start time and end time of saliva collection will be recorded to calculate the salivary flow rate per minute. | baseline, weeks 4,12 and 24 | 
| SjS participants: Change from baseline to the Schirmer's test | Schirmer's test is used to determine whether the eye produces enough tears to keep it moist especially for those who suffer from dry eye syndrome. A strip is placed in the lower eyelid for 5 minutes to assess tear production. After 5 minutes, the filter paper is removed and the distance between the leading edge of wetness and the initial fold is measured, using a millimeter ruler. Tear deficiency is defined as <5 mm wetting of the paper after 5 minutes. | baseline, weeks 4, 12 and 24 | 
| SjS participants: Sjögren's Tool for Assessing Response (STAR) response over time up to week 24 | STAR is a composite responder index, including in a single tool all main disease features, and designed for use as a key efficacy endpoint in SjS randomized clinical trials | baseline, weeks 4, 12 and24 | 
| MCTD: Change from baseline in articular and pulmonary domains of the Eular Sjögren's Syndrome Disease Activity Index (ESSDAI) | The ESSDAI is an established disease outcome measure for Sjögren's syndrome that classifies disease activity in 3-4 levels according to their severity (i.e., no, low, moderate, high), over each of 12 organ-specific domains. Participants with Mixed Connective Tissue Disease (MCTD) will complete the articular (from 0 no activity to 3 high activity) and pulmonary (from 0 no activity to 3 high activity) domains of the ESSDAI only. For MCTD participants, the maximum possible score is 21, where a higher score indicates more severe symptoms. A negative change score from baseline indicates improvement. | baseline, weeks 4, 8, 12 and 24 | 
| MCTD participants: Change from baseline in Forced Vital Capacity (FVC) | FVC is the total amount of air exhaled during the Forced expiratory volume (FEV) test measured through spirometry testing. FEV measures how much air a person can exhale during a forced breath. The amount of air exhaled may be measured during the first (FEV1), second (FEV2), and/or third seconds (FEV3) of the forced breath. A positive change from baseline is considered a favorable outcome. (FEV3) of the forced breath. FVC is the total amount of air exhaled during the FEV test. | baseline, weeks 12 and 24 | 
| MCTD participants: Change from baseline in Forced expiratory volume during the first second (FEV1) of a forced breath | FEV test measures how much air a person can exhale during a forced breath. The amount of air exhaled may be measured during the first (FEV1), second (FEV2), and/or third seconds (FEV3) of the forced breath. The test is measured through spirometry testing. A positive change from baseline is considered a favorable outcome. | baseline, weeks 12 and 24 | 
| MCTD participants: Change from baseline in Forced expiratory volume during the first two seconds (FEV2) of a forced breath | FEV test measures how much air a person can exhale during a forced breath. The amount of air exhaled may be measured during the first (FEV1), second (FEV2), and/or third seconds (FEV3) of the forced breath. The test is measured through spirometry testing. A positive change from baseline is considered a favorable outcome. | baseline, weeks 12 and 24 | 
| MCTD participants: Change from baseline in Forced expiratory volume during the first three seconds (FEV3) of a forced breath | FEV test measures how much air a person can exhale during a forced breath. The amount of air exhaled may be measured during the first (FEV1), second (FEV2), and/or third seconds (FEV3) of the forced breath. The test is measured through spirometry testing. A positive change from baseline is considered a favorable outcome. | baseline, weeks 12 and 24 | 
| MCTD participants: Change from baseline in the diffusing capacity of the lungs for carbon monoxide (DLCO) | DLCO is a measurement to assess the ability of the lungs to transfer gas from inspired air to the bloodstream. Inhaled carbon monoxide (CO) is used for this test due to its high affinity for hemoglobin. During a ten-second breath-hold, DLCO measures uptake of CO per time per CO pressure (cc of CO/sec/mm of Hg). A positive change from baseline is considered a favorable outcome. | baseline, weeks 12 and 24 | 
| MCTD participants: Change from baseline in King's Brief Interstitial Lung Disease (K-BILD) | The K-BILD questionnaire is a self-administered health-status questionnaire that has been developed in patients with interstitial lung diseases. It consists of 15 items in three domains: breathlessness and activities, psychological factors, and chest symptoms. Domain and total scores range from 0 to 100, with higher scores representing better health status. | baseline, weeks 4, 8, 12 and 24 | 
| MCTD participants: Change from baseline in Raynaud's Condition Score (RCS) | The RCS is participant's rating of difficulty considering number of attacks, duration, amount of pain, numbness, or other symptoms caused in the fingers (including painful sores) due to the Raynaud's phenomenon and impact of Raynaud's alone on use of hands every day. An 11-point Likert scale is used to rate the difficulty caused by the condition with 0 = no difficulty and 10 = extreme difficulty. Participants are asked to select the number that best describes their difficulty, with higher score indicating worse condition. | baseline, weeks 4, 12 and 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sicca Syndrome, Sjogren Syndrome, Connective Tissue Disease, Mixed, MCTD, Sharp Syndrome