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

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

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

Study Overview

• Status: Terminated
• Conditions: Sjogren Syndrome; Mixed Connective Tissue Disease
• Intervention / Treatment: Drug: MHV370; Drug: Placebo

Detailed Description

This was 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.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510000
      • Novartis Investigative Site
  • Jilin
    • Chang Chun, Jilin, China, 130021
      • Novartis Investigative Site
• Germany
  • Berlin, Germany, 10117
    • Novartis Investigative Site
• Hungary
  • Debrecen, Hungary, 4032
    • Novartis Investigative Site
  • Fejer
    • Szekesfehervar, Fejer, Hungary, 8000
      • Novartis Investigative Site
• Poland
  • Lublin, Poland, 20-954
    • Novartis Investigative Site
  • Warszawa, Poland, 02 637
    • Novartis Investigative Site
  • Podlaskie
    • Bialystok, Podlaskie, Poland, 15 707
      • Novartis Investigative Site
• Spain
  • Madrid, Spain, 28041
    • Novartis Investigative Site
• Taiwan
  • Kaohsiung, Taiwan, 81346
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / 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

What is the study measuring?

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. The score range is 0 - 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. Only participants with evaluable records are included.	Baseline, Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
SjS and MCTD Participants: Maximum Observed Plasma Concentrations (Cmax) of MHV370 at Steady State	Cmax is the maximum (peak) observed plasma concentration of MHV370 after single dose administration. Pharmacokinetic (PK) parameters were calculated based on MHV370 plasma concentrations determined by a validated liquid chromatography and tandem mass spectrometry (LC-MS/MS) method with a lower limit of quantification of 1.0 ng/mL. Cmax was determined using non-compartmental methods.	pre-dose, 0.5, 1, 2 ,4 and 6 hours after dosing at week 4
SjS and MCTD Participants: Area Under the Plasma Concentration-time Curve From Time Zero to 6 Hours (AUC0-6h) of MHV370	The AUC from time zero to the 6-hours post-dose sampling time. Pharmacokinetic (PK) parameters were calculated based on MHV370 plasma concentrations determined by a validated liquid chromatography and tandem mass spectrometry (LC-MS/MS) method with a lower limit of quantification of 1.0 ng/mL. AUClast was determined using non-compartmental methods.	pre-dose, 0.5, 1, 2 ,4 and 6 hours after dosing at week 4
SjS and MCTD Participants: Time to Reach Maximum Plasma Concentrations (Tmax) of MHV370 at Steady State	Tmax is the time to reach maximum (peak) plasma concentration of MHV370 after single dose administration. Pharmacokinetic (PK) parameters were calculated based on MHV370 plasma concentrations determined by a validated liquid chromatography and tandem mass spectrometry (LC-MS/MS) method with a lower limit of quantification of 1.0 ng/mL. Tmax was determined using non-compartmental methods.	pre-dose, 0.5, 1, 2 ,4 and 6 hours after dosing at week 4
SjS and MCTD Participants: Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Scale	The Functional Assessment of Chronic Illness Therapy-Fatigue (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.	Baseline, Weeks 4, 8, 12, 20 and 24
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. The score range is 0 - 123, where a higher ESSDAI 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 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 were collected over 5 minutes from participants. All assessments were performed at a fixed time of the day to minimize fluctuations related to the circadian rhythm of salivary flow and composition. Participants were instructed not to eat, drink or smoke for 90 minutes before the assessment. The start time and end time of saliva collection were recorded to calculate the salivary flow rate per minute. Only participants with evaluable records are included.	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, Week 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 Domain Point Definition of response. Points are assigned in the following 5 domains, if the corresponding criteria are met: Systemic activity, if decrease in clin ESSDAI ≥ 3 points: 3 points; Patient reported outcome, if decrease in ESSPRI ≥ 1 point or 15%: 3 points; Lacrimal gland function (assessed by Schirmer's test), if abnormal score at baseline: increase ≥ 5 mm from baseline OR if normal score at baseline: no change to abnormal: 1 point; Salivary gland function (assessed by unstimulated salivary flow), if increase ≥ 25% from baseline: 1 point; Biological (assessed by serum IgG levels), if decrease ≥ 10%: 1 point The Total Score is the sum of all 5 domain scores, ranging from 0 to 9 points. A STAR responder is defined as ≥ 5 points in the Total Score.	Baseline, Week 4, 12 and 24
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) completed 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 score range is 0-21, 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)	Forced Vital Capacity (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. A positive change from baseline is considered a favorable outcome.	Baseline, Week 12
MCTD Participants: Change From Baseline in Forced Expiratory Volume During the First Second (FEV1) of a Forced Breath	FEV1 (forced expiratory volume in one second) is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation, measured through spirometry testing. A positive change from baseline in FEV1 is considered a favourable outcome.	Baseline, Week 12
MCTD Participants: Change From Baseline in Forced Expiratory Volume During the First Two Seconds (FEV2) of a Forced Breath	FEV2 (forced expiratory volume in two seconds) is the amount of air which can be forcibly exhaled from the lungs in the first two seconds of a forced exhalation, measured through spirometry testing. A positive change from baseline in FEV2 is considered a favourable outcome.	Baseline, Week 12
MCTD Participants: Change From Baseline in Forced Expiratory Volume During the First Three Seconds (FEV3) of a Forced Breath	FEV3 (forced expiratory volume in three seconds) is the amount of air which can be forcibly exhaled from the lungs in the first three seconds of a forced exhalation, measured through spirometry testing. A positive change from baseline in FEV3 is considered a favourable outcome.	Baseline, Week 12
MCTD Participants: Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO)	Diffusing capacity of the lungs for carbon monoxide (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. The outcome is presented as percentage of predicted DLCO value.	Baseline, Week 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. 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 Raynaud's Condition score (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

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

• A Plain Language Trial Summary is available on www.novctrd.com

Study record dates

Study Major Dates

• Study Start (Actual): November 30, 2021
• Primary Completion (Actual): February 7, 2023
• Study Completion (Actual): March 7, 2023

Study Registration Dates

• First Submitted: July 26, 2021
• First Submitted That Met QC Criteria: July 26, 2021
• First Posted (Actual): August 3, 2021

Study Record Updates

• Last Update Posted (Estimated): October 9, 2024
• Last Update Submitted That Met QC Criteria: October 7, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: Sjogren Syndrome; MCTD; Sicca Syndrome; Connective Tissue Disease, Mixed; Sharp Syndrome
• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Autoimmune Diseases; Eye Diseases; Disease; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Arthritis; Stomatognathic Diseases; Mouth Diseases; Lacrimal Apparatus Diseases; Arthritis, Rheumatoid; Xerostomia; Salivary Gland Diseases; Dry Eye Syndromes; Syndrome; Connective Tissue Diseases; Sjogren's Syndrome; Mixed Connective Tissue Disease
• Other Study ID Numbers: CMHV370A12201; 2020-004937-19 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No