Safety and Efficacy of ULSC on Disease Severity and Steroid Tapering in Participants With Dermatomyositis/ Polymyositis (DM/PM), Also Known as Idiopathic Inflammatory Myopathy (IIM)

Phase 3RecruitingNCT07160205

Restem, LLC.40 enrolled

Overview

The goal of this clinical trial is to learn about how an umbilical cord lining-derived stem cell (ULSC) product performs when treating Dermatomyositis/Polymyositis (DM/PM), also known as idiopathic inflammatory myopathy (IIM) in adults. It will assess safety and efficacy in relieving symptoms of DM/PM with ULSC administered in three intravenous (IV) doses of 150 million cells per dose. The main questions that this study plans to answer are: * Is ULSC as safe as placebo (a look-alike saline without cells) in repeated IV infusion? * Does ULSC improve symptoms of DM/PM after three doses? Researchers will compare ULSC to placebo and evaluate changes from baseline (before first dose) to after each dose and after all three doses are completed per treatment study period. * For participants undergoing steroid (e.g., prednisone) therapy for DM/PM, does ULSC allow their steroid dose to be reduced? Does ULSC reduce need for rescue therapy? Participants will have been diagnosed with either DM or PM: * Diagnosed according to the EULAR/ACR 2017 Classification Criteria for idiopathic inflammatory myositis (IIM), which includes DM and PM. * Positive for myositis-associated antibody or undergone evaluation to exclude mimics. Participants in this study will: * Participate for total of 25 months with 15 in-person clinic visits and 8 virtual visits on phone or video call. * Receive both ULSC and placebo for a total of 6 IV infusions (260 mL) 3 months apart. * Receive 3 doses of ULSC and 3 doses placebo in either of two sequences, as assigned: ULSC first and placebo second, or placebo first and ULSC second. * If undergoing steroid therapy, will have steroid dose taper prescribing lower doses starting two weeks after the second infusion. * Return for follow-up visits after each dose and up to 12 months after final dose. * Have follow-ups including self-reported questionnaires, physical exam, muscle strength and endurance tests, blood tests, pulmonary function tests, and other assessments.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Participants will be ≥18 years old. 2. Diagnosis of idiopathic inflammatory myositis (IIM) based on 2017 EULAR/ACR Classification Criteria for adult IIM, corresponding to a score of ≥ 5.5 (≥ 6.7 with muscle biopsy). 3. Active disease as defined by any one of the following test results: 1. Elevated Creatine Kinase (CK) or Aldolase (more than 1.5 x the upper limit of normal) at screening, OR 2. MRI positive for active, muscle inflammation within 12 weeks prior to screening, OR 3. EMG read as active myositis within 12 weeks prior to screening, OR 4. muscle biopsy obtained within 12 weeks of the screening showing active inflammatory disease. 4. Muscle weakness or active cutaneous manifestations of dermatomyositis assessed at Screening and documented with either of the following scores: 1. Bilateral MMT-8 score of ≤142/150, OR 2. CDASI Total Activity score of ≥ 7. 5. Participants must be receiving standard of care treatment with one or more immunosuppressants or at least 5 mg prednisone (or corticosteroid equivalent). 1. Immunosuppressive doses should be stable for at least 12 weeks prior to enrollment. Participants must remain on stable immunosuppressive therapy for the duration of the trial unless discontinuation is warranted due to toxicity or another clinical reason. 2. Hydroxychloroquine (HCQ) doses should be stable for at least 12 weeks prior to enrollment. 3. Steroid doses should be stable for at least 4 weeks prior to enrollment. At screening and enrollment, maximum dose allowed is 25 mg/day prednisone (or corticosteroid equivalent). 4. Allowed immunosuppressants include: methotrexate, azathioprine, mycophenolate, cyclosporine, IVIG, and others to be evaluated at the discretion of the investigator. 6. Participants will either be: 1. positive for a myositis-associated antibody, OR 2. will have undergone evaluation to exclude mimics, as deemed appropriate by the Investigator. Note: The minimum workup to be performed on all prospective participants to exclude mimics is as standardly followed, which may include: * Medical history and physical exam to determine the clinical course and progression of symptoms, the distribution of weakness, and the absence of features of myelopathy, neuropathy, neuromuscular disease, myotonic dystrophy, and congenital myopathy; * Elevated Creatine Kinase (CK) or Aldolase levels in blood; * Electromyography (EMG) and/or MRI of clinically affected 99+proximal muscle group; * Myositis-specific and myositis-associated autoantibodies in blood; * Muscle biopsy with characteristic features of IIM and excluding features of muscular dystrophy, metabolic myopathies, drug-induce myopathy, inclusion body myopathy, and necrotizing myopathy; * Blood tests for exclusion of HIV, Hepatitis B (HBV), and Hepatitis C (HCV). \[Screening tests are done for HIV ELISA, HBs Ag, HBc Ab, and HCV Ab with reflex for HCV RNA (PCR) for exclusion criteria.\] 7. Adequate pulmonary function, defined as saturated oxygen (SpO2 ≥ 94%) on room air. 8. Left ventricular ejection fraction (LVEF) ≥ 30% as assessed by echocardiogram (ECHO) or multigated acquisition (MUGA) scan performed within 8 weeks prior to Screening. 9. Participants must have the ability to comply with the requirements of the study. 10. All participants of reproductive age/capacity will be required to use adequate contraception, defined as at least one form of a highly effective contraceptive (i.e., condoms, hormonal birth control, IUD), with any partners during the study period and for at least three months beyond the study period, for safety. 11. Participant will have the ability to understand and provide written informed consent. Exclusion Criteria: The presence of any of the following criteria excludes a participant from study enrollment: 1. A diagnosis of inclusion body myositis, juvenile DM or PM, myositis in the context of significant autoimmune rheumatologic disease. 2. Diagnosis of IIM as part of an overlap syndrome (except overlap with Sjogren's syndrome). 3. Initiation of Rituxan (rituximab) treatment within 12 weeks of randomization. If participant is already on Rituxan, they must remain on a stable dose throughout the trial. 4. Use of other biologic or investigational drug within 6 half-lives for the agent. 5. Diagnosis of myositis-associated interstitial lung disease or cardiac involvement sufficient to limit participation in the trial in the discretion of the PI. 6. End-stage IIM with irreversible muscle involvement seen on biopsy. 7. Patients with predominant muscle atrophy secondary to uncontrolled or chronic DM or PM, based on clinical, biochemical, and/or radiologic assessment, despite previous optimized treatment. 8. Non-immune myopathies. 9. Cancer associated with myositis. 10. Hypersensitivity to study product components including history of hypersensitivity to dimethyl sulfoxide (DMSO). 11. Pregnant or lactating participants. 12. Concomitant severe cardiac, pulmonary disease, active infection, or other conditions that preclude assessment of safety and efficacy of the study product. 13. Anticipated need for surgery during the trial period. 14. A history of prevalent noncompliance with medical therapy. 15. Recipient of an organ transplant. 16. Neutropenia \[absolute neutrophil count \<1,800/mm\^3 (or \<1,000/mm\^3 in African-American participants)\]. 17. Severe impairment in renal function (estimated glomerular filtration rate \<30 ml/kg\*min). 18. Recent or planned use of vaccination with live attenuated viruses. 19. Active cancer or prior diagnosis of cancer within the past 2 years, except non-melanoma skin cancer and carcinoma in situ of cervix Potential participants diagnosed with IIM \<3 years before screening will have mandatory evaluation for cancer. 20. Participants with current or prior hepatitis B infection that could be at risk for reactivation. \[For eligibility, screening test results must be HBsAg (DNA) negative and anti-HBc (core antibody total) negative).\] 21. Participant with HIV or active Hepatitis C. \[For eligibility, the following screening tests must have negative or non-reactive results: HIV ELISA, HCV Ab with reflex for HCV RNA (PCR); if HCV Ab test is positive, exclude if HCV RNA (PCR) is positive.\] 22. Condition that would impair an assessment of muscle strength, including neurological disorders such as Parkinson's disease or severe musculoskeletal condition. 23. Any other condition that, in the judgment of the Investigator or Sponsor, would be a contraindication to enrollment, study product administration, or follow-up.

Outcomes

Primary Outcomes

Safety based on Adverse Events (AEs) and Serious Adverse Events (SAEs) that begin during or following treatment infusion.

Cumulative listing of all AEs/SAEs per cohort with descriptive statistics for categorical variables and count variables to compare between ULSC and Placebo, with emphasis on All SAEs and AEs/SAEs suspected to be treatment infusion-related.

Time frame: Each visit from Day 0, 7 days, and 30 days after each infusion, and all follow-up visits up to 12 months after the final treatment infusion.

Efficacy based on Total Improvement Score (TIS, expressed as continuous variable) in the 2016 ACR/EULAR Myositis Response Criteria

Total Improvement Score (TIS) as continuous variable (scale of 0 to 100 points) will be assessed; TIS is a weighted average of the sub-scores in the 6 core set measures that comprise the validated outcome measure in the 2016 ACR/EULAR Myositis Response Criteria.

Time frame: From baseline (i.e., before first dose per treatment) to 7 months (i.e., one month after the third/final dose per treatment) for each treatment group and each study period.

Secondary Outcomes

Need for Rescue Therapy (Incidence)

The incidence of need for rescue therapy will be assessed by the number of participants that require administration of rescue therapy.

Time frame: From baseline to 7 months for both study periods.

Need for Rescue Therapy (Time)

Need for rescue therapy will be assessed in terms of the time to rescue therapy, i.e. time from the first dose of study treatment to the first administration of rescue therapy required.

Time frame: From baseline to 7 months for both study periods.

Glucocorticoid Dose (prednisone equivalents per day) Tapering

Changes from baseline in glucocorticoid dose expressed in prednisone equivalents (mg/day) will be assessed as a measure of steroid tapering over time.

Time frame: From baseline to 4 months and 7 months for both study periods.

Total Improvement Score (TIS) improvement category (minimal, moderate, or major improvement) in the 2016 ACR/EULAR Myositis Response Criteria

Response relative to baseline will be assessed in terms of Total improvement category (minimal TIS ≥20, moderate TIS ≥40, or major TIS ≥60). TIS is a weighted average of the sub-scores in the 6 core set measures that comprise the validated outcome measure in the 2016 ACR/EULAR Myositis Response Criteria.

Time frame: From baseline to 7 months for both study periods.

Total Improvement Score (TIS, expressed as continuous variable) in the 2016 ACR/EULAR Myositis Response Criteria after each repeat dose

Response to repeat dosing will be assessed by TIS (scale of 0 to 100 points) at 1 month after each repeat dose: TIS at 1 month (after 1 dose), 4 months (after 2 doses), and 7 months (after 3 doses).

Time frame: From baseline to 1 month, 4 months, and 7 months for both study periods.

Modified Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) Activity Score

The mean changes in the modified CDASI activity score (scale of 0-100) will be assessed. The CDASI is a partially validated, clinician-scored, 1-page outcome measure for assessing skin disease in DM patients. It evaluates the skin in 15 anatomic locations and provides two separate scores based on activity and damage. The CDASI activity score reflects the presence and severity of active skin inflammation, and it is the sum of scores for erythema, scaling, ulceration/erosion, and activity due to Gottron's papules on the hands, recent hair loss, and periungual changes. Higher scores indicate greater disease severity.

Time frame: From baseline to 7 months for both study periods.

Modified Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) Damage Score

The mean changes in the modified CDASI damage score (scale of 0-32) will be assessed. The CDASI is a partially validated, clinician-scored, 1-page outcome measure for assessing skin disease in DM patients. It evaluates the skin in 15 anatomic locations and is comprised of two separate scores based on activity and damage. The CDASI damage score reflects the chronic manifestations of skin disease, and it is the sum of scores for poikiloderma and calcinosis and damage due to Gottron's papules on the hands, recent hair loss, and periungual changes. Higher scores indicate greater disease severity.

Time frame: From baseline to 7 months for both study periods.

Myositis Disease Activity Assessment Tool (MDAAT)

The mean changes in scores on the MDAAT will be assessed. The MDAAT utilizes Visual Analogue Scale (VAS). The VAS is a 10-point scale (left end of line = no evidence of disease activity, midpoint of line = moderate disease activity, and right end of line = extreme or maximum disease activity) which the physician assesses, for each of several pre-designated extra-muscular organ systems. The common format is a horizontal bar or line. Physicians assess each designated organ system based on how active the patient's disease has been within the prior four weeks. These VAS ratings are determined with the help of a listed set of clinical and laboratory findings.

Time frame: From baseline to 7 months for both study periods.

Myositis Damage Index (MDI) Extent Score

The mean changes in scores on the myositis damage index (MDI) extent score will be assessed. Each organ system is scored 0 or 1 (0 means never present and 1 means present for at least 6 months). The total extent score is the sum of all items scored across all systems divided by the total possible maximum score (scale of 0 to 38 in adults).

Time frame: From baseline to 7 months for both study periods.

Myositis Damage Index (MDI) Severity Score

The mean changes in scores on the myositis damage index (MDI) Severity Score will be assessed. Clinician rates the severity of the damage of each organ system using a 10 cm visual analogue scale (VAS) from 0 to 10 (0 means no damage and 10 means extreme damage). Final score is the sum of all systems (scale of 0 to 110 for all 11 systems).

Time frame: From baseline to 7 months for both study periods.

Cutaneous Dermatomyositis Investigator Global Assessment (CDM-IGA)

The mean changes in scores on the CDM-IGA will be assessed. The CDM-IGA observes the skin on 11 areas of the body, which are scored on a scale of 0 to 4 based on color and extent of the active cutaneous disease. The final CDM-IGA score is equal to the highest scoring characteristic.

Time frame: From baseline to 7 months for both study periods.

Self-reported physical function capability measured by PROMIS PF-20a

The mean change in self-reported physical function capability in each treatment group as measured by PROMIS PF-20 will be assessed. The PROMIS PF-20 measures asks 20 questions about the functioning of the upper extremities (dexterity), lower extremities (walking or mobility), and central regions (neck, back), as well as instrumental activities of daily living, such as running errands. The PROMIS PF-20a provides a single Physical Function capability score and assesses current function.

Time frame: From baseline to 7 months for both study periods.

Glucocorticoid Dose (prednisone equivalents per day) Tapering after repeat doses of study treatment

The mean change from baseline in glucocorticoid dose expressed in prednisone equivalents (mg/day) will be assessed as a measure of steroid tapering after two and three doses of study treatment.

Time frame: Baseline, from 3 months to 4 months, and from 6 months to 7 months, for each study period.

Time to achieve maximum TIS improvement category

The time (months) from study treatment initiation to when the maximum improvement category is achieved in TIS will be assessed. The improvement in each subject will be categorized as minimal (≤ 20 points change), moderate (21 - 40 points), or major (\> 40 points).

Time frame: From baseline to within 7 months for each study period.

Time to confirmed deterioration in the TIS expressed as continuous variable

The time (months) from study treatment initiation to confirmed deterioration in TIS (continuous variable, scale of 0 to100) will be assessed.

Time frame: From baseline to each visit within 7 months for each study period.

Pulmonary function test - Forced Expiratory Volume in one second (FEV1)

Pulmonary function will be evaluated for normal or abnormal based on the Forced Expiratory Volume in one second (FEV1, Liters) measured by spirometry. FEV1 measures how quickly air can be exhaled in the first second of a forced exhalation. A low FEV1 indicates difficulty with quick air flow out of the lungs, such as in obstructive lung disease. Changes will be assessed.

Time frame: From baseline to 7 months for both study periods.

Pulmonary function test - Forced Vital Capacity (FVC)

Pulmonary function will be evaluated for normal or abnormal based on the Forced Vital Capacity (FVC, Liters) measured by spirometry. FVC measures the maximum amount of air a person can forcefully blow out after taking the deepest possible breath. A low FVC can result from poor effort or conditions that restrict the ability of the lungs to fill, such as in restrictive lung diseases. Changes will be assessed.

Time frame: From baseline to 7 months for both study periods.

Pulmonary function test - FEV1/FVC ratio

Pulmonary function will be evaluated for normal or abnormal based on the ratio of spirometry measurements of FEV1/FVC (%). The FEV1/FVC ratio helps differentiate between obstructive lung diseases (like asthma or COPD, which lead to disproportionately low FEV1) that result in low FEV1/FVC ratio, and restrictive lung diseases (like pulmonary fibrosis, which lead to low FVC) that can have FEV1/FVC ratio appear normal or high. Changes will be assessed.

Time frame: From baseline to 7 months for both study periods.

Pulmonary function test - Peak Expiratory Flow (PEF)

Pulmonary function will be evaluated for normal or abnormal based on the Peak Expiratory Flow (PEF, Liters per second) measured by spirometry. PEF measures the maximum speed (flow rate) at which air can be exhaled from the lungs after a deep breath. A high PEF indicates strong lung airflow, and a low PEF suggests potential issues like airway obstruction. Changes will be assessed.

Time frame: From baseline to 7 months for both study periods.

Pulmonary function test - Diffusing Capacity of the Lungs for carbon monoxide (DLCO)

Pulmonary function will be evaluated for normal or abnormal based on the Diffusing Capacity of the Lungs for Carbon monoxide (DLCO, %). DLCO measures the efficiency of gas exchange in the lungs. A normal DLCO indicates healthy gas exchange in the lungs. A low DLCO may suggest possible reduction in the surface area for gas exchange or possible issue with blood flow or blood vessels in the lungs. DLCO is typically measured along with other pulmonary function tests, such as spirometry. Changes will be assessed.

Time frame: From baseline to 7 months for both study periods.

Left ventricular function evaluated by transthoracic echocardiography

Left ventricular function will be evaluated for normal or abnormal based on transthoracic echocardiography (TTE) parameters measuring left ventricular ejection fraction (LVEF), left ventricular end diastolic volume (LVEDV), and left ventricular end systolic volume (LVESV).

Time frame: From baseline to 7 months for both study periods.

Functional Index-3 (FI-3) test

Changes in endurance of repetitive muscle activity will be assessed by the Functional Index-3 (FI-3) test. The FI-3 is a validated method for assessing functional disability (i.e., muscle endurance and stamina) in patients with DM or PM. The assessment consists of 3 tasks, performed either unilaterally or bilaterally, to test shoulder, neck, and hip flexion, with a total score (0-100) computed from the task results. For this study, neck (30), arm (60), and leg lifts (60) on dominant side will be tested using metronome.

Time frame: From baseline to 7 months for both study periods.

Myositis Antibody Panel

Changes in disease activity will be assessed using the extended myositis specific antibody panel IgG titers as biomarkers of myositis disease activity.

Time frame: From baseline to 7 months for both study periods.

Safety and Efficacy of ULSC on Disease Severity and Steroid Tapering in Participants With Dermatomyositis/ Polymyositis (DM/PM), Also Known as Idiopathic Inflammatory Myopathy (IIM)

Overview

Conditions

Interventions

Eligibility

Locations (2)

Outcomes

Primary Outcomes

Secondary Outcomes