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

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04988087

Collaborator

(none)

Enrollment

Locations

Arms

Anticipated Duration (Months)

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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).

Condition or Disease	Intervention/Treatment	Phase
Sjogren Syndrome Mixed Connective Tissue Disease	Drug: MHV370 Drug: Placebo	Phase 2

Detailed Description

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 will first undergo 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 will be up to 34 weeks. Approximately 60 participants will be enrolled: 48 participants with SjS will be randomized in a 1:1 ratio to MHV370 or placebo and 12 participants with MCTD will be randomized in a 1:1 ratio to MHV370 or placebo.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

60 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Nov 30, 2021

Anticipated Primary Completion Date :

Dec 20, 2023

Anticipated Study Completion Date :

Jan 31, 2024

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

SjS participants: Change from baseline in Eular Sjögren's Disease Activity Index (ESSDAI) after 24 weeks of treatment [baseline, week 24]
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.
MCTD participants: Change from baseline in physician's global assessment scale (PhGA) after 24 weeks of treatment [baseline, week 24]
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.

Secondary Outcome Measures

SjS and MCTD participants: Maximum Observed Blood Concentrations (Cmax) of MHV370 at steady state [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]
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.
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 [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]
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.
SjS and MCTD participants: Time to Reach Maximum Blood Concentrations (Tmax) of MHV370 at steady state [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]
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.
SjS and MCTD participants: Change from baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scale [baseline, weeks 4, 8, 12, 20 and 24]
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.
SjS and MCTD participants: Change from baseline in Physician Global Assessment (PhGA) [SjS participants: baseline, weeks 4, 8, 12, 20 and 24. MCTD participants: baseline, weeks 4, 8, 12, and 20.]
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: Change from baseline in Eular Sjögren's Syndrome Disease Activity Index (ESSDAI) [baseline, weeks 4, 8, 12 and 20]
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.
SjS participants: Change from baseline in Eular Sjögren's Syndrome Patient Reported Index (ESSPRI) [baseline, weeks 4, 8, 12, 20 and 24]
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.
SjS participants: Change from baseline to the salivary flow rate [baseline, weeks 4,12 and 24]
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.
SjS participants: Change from baseline to the Schirmer's test [baseline, weeks 4, 12 and 24]
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.
SjS participants: Sjögren's Tool for Assessing Response (STAR) response over time up to week 24 [baseline, weeks 4, 12 and24]
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
MCTD: Change from baseline in articular and pulmonary domains of the Eular Sjögren's Syndrome Disease Activity Index (ESSDAI) [baseline, weeks 4, 8, 12 and 24]
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.
MCTD participants: Change from baseline in Forced Vital Capacity (FVC) [baseline, weeks 12 and 24]
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.
MCTD participants: Change from baseline in Forced expiratory volume during the first second (FEV1) of a forced breath [baseline, weeks 12 and 24]
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.
MCTD participants: Change from baseline in Forced expiratory volume during the first two seconds (FEV2) of a forced breath [baseline, weeks 12 and 24]
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.
MCTD participants: Change from baseline in Forced expiratory volume during the first three seconds (FEV3) of a forced breath [baseline, weeks 12 and 24]
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.
MCTD participants: Change from baseline in the diffusing capacity of the lungs for carbon monoxide (DLCO) [baseline, weeks 12 and 24]
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.
MCTD participants: Change from baseline in King's Brief Interstitial Lung Disease (K-BILD) [baseline, weeks 4, 8, 12 and 24]
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.
MCTD participants: Change from baseline in Raynaud's Condition Score (RCS) [baseline, weeks 4, 12 and 24]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Guangzhou	Guangdong	China	510000
2	Novartis Investigative Site	Chang Chun	Jilin	China	130021
3	Novartis Investigative Site	Shanghai		China	200127
4	Novartis Investigative Site	Berlin		Germany	10117
5	Novartis Investigative Site	Szekesfehervar	Fejer	Hungary	8000
6	Novartis Investigative Site	Debrecen		Hungary	4032
7	Novartis Investigative Site	Szeged		Hungary	6720
8	Novartis Investigative Site	Bialystok	Podlaskie	Poland	15 707
9	Novartis Investigative Site	Lublin		Poland	20-954
10	Novartis Investigative Site	Warszawa		Poland	02 637
11	Novartis Investigative Site	Barcelona	Catalunya	Spain	08035
12	Novartis Investigative Site	Barcelona		Spain	08041
13	Novartis Investigative Site	Madrid		Spain	28041
14	Novartis Investigative Site	Madrid		Spain	28046
15	Novartis Investigative Site	Bern		Switzerland	3010
16	Novartis Investigative Site	Kaohsiung		Taiwan	81346
17	Novartis Investigative Site	Taichung		Taiwan	40705
18	Novartis Investigative Site	Taoyuan		Taiwan	33305
19	Novartis Investigative Site	Bradford	West Yorkshire	United Kingdom	BD5 0NA
20	Novartis Investigative Site	Swindon		United Kingdom	SN3 6BB