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NCT Number: NCT05832034

Add-on Intravenous Immunoglobulins in Early Myositis

In patients with myositis early immunomodulation by intensive treatment ("hit-early/hit-hard" principle) may induce faster reduction of disease activity and prevent chronic disability. Intravenous immunoglobulin (IVIg) in addition to standard treatment with glucocorticoids may be beneficial for this purpose: add-on IVIg improved symptoms in steroid-resistant myositis, and first-line monotherapy IVIg led to a fast and clinically relevant response in a pilot study in nearly 50% of patients with myositis.

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Key information

Conditions

Inflammatory Myopathy, Idiopathic Antisynthetase Syndrome Connective Tissue Diseases Dermatomyositis Immune-Mediated Necrotizing Myopathy Muscular Diseases Musculoskeletal Diseases Myositis Nervous System Diseases Neuromuscular Diseases Polymyositis Skin Diseases Skin and Connective Tissue Diseases

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2 / Phase 3

Primary location

Department of Neurology, Amsterdam UMC, location AMC

Amsterdam, North Holland, 1105 AZ, Netherlands

About this study

Considering the known effects of IVIg in idiopathic inflammatory myopathies (IIM), both as add-on therapy in refractory patients, as well as monotherapy in newly diagnosed IIM, we conducted a phase-2 double-blind placebo-controlled randomized trial to investigate the effect of add-on IVIg in patients with newly diagnosed IIM, who are treated with monotherapy prednisone.

Objective:

The primary aim of this trial is to examine whether the addition of early administered IVIg to standard therapy with prednisone in patients with newly diagnosed myositis leads to an improved clinical response after 12 weeks, compared to prednisone and placebo. Clinical response will be measured as the difference of the mean TIS after 12 weeks between intervention and control groups.

The secondary aims are to examine whether the intervention leads to a shorter time to improvement, and sustained positive effects on health-related quality of life, physical activity and fatigue, and a sustained reduction of muscle MRI abnormalities, as assessed up to 52 weeks.

Following a screening visit at the outpatient clinic, patients will be admitted to the neurology ward of the Amsterdam University Medical Center (AUMC) for the first infusion of study treatment. The remaining study medication will be administered at home, according to routine clinical practice for IVIg treatment in neuromuscular disorders in the Netherlands. A second and third study treatment will be administered at home after 4 and 8 weeks. At baseline and after 4, 8, 12, 26 and 52 weeks outcome assessments will be performed at the outpatient clinic. The outpatient study clinic visits at baseline and after 4, 12, 26 and 52 weeks will be combined with regular outpatient clinic visits.

The additional burden related to outcome assessments will consist of MRI muscle imaging after 12 weeks, blood sampling after 2, 4, 6, and 10 weeks and filling in questionnaires at baseline and after 4, 8, 12, 26 and 52 weeks. In addition, participants are asked to wear a watch three times in a period of 12 weeks and after 26 weeks.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Adult patients (≥ 18 years) with IIM, according to diagnostic criteria:
  • Dermatomyositis
  • Polymyositis
  • Anti-synthetase syndrome
  • Immune mediated necrotizing myopathy
  • Overlap myositis
  • Disease duration < 12 months
  • Minimal disability defined as at least 10% loss on Manual Muscle Testing (MMT) and abnormal scores on two other Core Set Measures (CSMs) of the international Myositis Assessment and Clinical Studies (IMACS) group (see 'Primary and secondary outcomes').
  • Patients are eligible for inclusion if they are treatment-naive, or if there is no clinical evident response (as carefully judged by the treating physician at a screening visit) to prior treatment with:
  • High dosed glucocorticoids, such as dexamethasone (e.g. 40 mg per day up to 4 days) or intravenous methylprednisolone (e.g. 1000 mg daily for three days), within 1 week prior to screening visit.
  • Daily dosed prednisone 1 mg/kg, or equivalent, used for up to 2 weeks prior to screening visit.
  • Treatment with low-dosed prednisone (max 20 mg daily) up to three months prior to screening visit.
  • Treatment with biologicals or other immunosuppressive or immunomodulatory treatment when meeting all of the following criteria:
  • Stable dose for the last 6 months
  • The biological or other immunosuppressive or immunomodulatory treatment has been approved for a non-muscular condition (e.g. hematological condition, eczema)
  • The biological or other immunosuppressive or immunomodulatory treatment is not known to induce inflammatory myopathy
  • Signed informed consent

Exclusion criteria

A potentially eligible patient who meets any of the following criteria will be excluded from participation in this study:

  • Severe muscle weakness (i.e. bedridden, severe dysphagia requiring a feeding tube, or respiratory muscle weakness (forced vital capacity below 50% of predicted in upright position)) necessitating more intensive treatment than standard glucocorticoids from the start.
  • Related to IVIg:
  • History of thrombotic episodes within 10 years prior to enrolment
  • Known allergic reactions or other severe reactions to any blood-derived product
  • Known Immunoglobulin A (IgA) deficiency and IgA serum antibodies
  • Pregnancy or trying to conceive
  • Use of nephrotoxic medication
  • Conditions that are likely to interfere with:
  • Compliance (legally incompetent and/or incapacitated patients are excluded), or,
  • Evaluation of efficacy (e.g. due to severe pre-existing disability as a result of any other disease than myositis or due to language barrier)
  • Immunosuppressive medication or immunomodulatory treatment within the last 3 months (e.g. azathioprine, methotrexate, mycophenolate mofetil, tacrolimus, cyclophosphamide, cyclosporine, IVIg, biologicals, Janus kinase inhibitors, plasmapheresis).

Treatment and study plan

Immune Globulin Intravenous (Human)

Drug

IVIg is 2 g/kg over 2 to 5 days at baseline, followed by 2 g/kg IV in 2 to 5 days after 4 and 8 weeks. The rate of infusion is controlled by means of an infusion pump. The first dosage (30 grams IVIg) will be administered on the neurology ward.

Other names: Nanogam

Placebo

Drug

Placebo infusions, containing sodium chloride 0.9%, at baseline and after 4 and 8 weeks.

Other names: Sodium chloride or saline 0.9%

Primary outcomes

  1. Change in Total Improvement Score (TIS)

    Time frame: Week 12

    The primary outcome is the Total Improvement Score (TIS) of the myositis response criteria after 12 weeks, measured as the difference of the mean TIS after 12 weeks between intervention and control groups. Total Improvement Score (TIS) is based on 6 validated core set measures (CSMs), which each determine disease activity as defined by the International Myositis Assessment and Clinical Studies (IMACS) group. TIS ranges between 0 and 100 and corresponds to a degree of improvement; higher scores correspond to a greater degree of improvement.

Secondary outcomes

  1. Total Improvement Score (IMACS).

    Time frame: TIS will be assessed at t = 0, and after 4, 8, 12, 26 and 52 weeks

    Total Improvement Score (TIS) is based on 6 validated core set measures (CSMs), which each determine disease activity as defined by the International Myositis Assessment and Clinical Studies (IMACS) group. TIS ranges between 0 and 100 and corresponds to a degree of improvement; higher scores correspond to a greater degree of improvement.

  2. Moderate improvement proportion

    Time frame: Examined at week 12

    This is defined as proportion of patients in each treatment group that reaches moderate improvement, i.e. Total Improvement Score of ≥40. Total Improvement Score is based on 6 validated core set measures (CSMs), which each determine disease activity as defined by the International Myositis Assessment and Clinical Studies (IMACS) group.

  3. Time to response (TIS>40 points)

    Time frame: Will be examined at week 4, 8, 12, 26 and 52 weeks.

    This is defined as the time is taken to reach a Total Improvement Score > 40 points.Total Improvement Score is based on 6 validated core set measures (CSMs), which each determine disease activity as defined by the International Myositis Assessment and Clinical Studies (IMACS) group.

  4. Core set measures (CSM) - physician global activity (PhGA)

    Time frame: CSMs will be assessed at baseline, week 4, 8, 12, 26 and 52.

    • physician global activity (PhGA): assessment of global disease activity on a 10 cm Visual Analogue Scale (VAS) by the treating physician. 0 = no disease activity, 10 most activity

    On a total of 6 CSM

  5. Core set measures (CSM) - patient global activity (PGA)

    Time frame: CSMs will be assessed at baseline, week 4, 8, 12, 26 and 52.

    • patient global activity (PGA): assessment of global disease activity on a 10 cm VAS by the patient. 0 = no disease activity, 10 most activity On a total of 6 CSM

  6. Core set measures (CSM) - Manual Muscle Testing (MMT)

    Time frame: CSMs will be assessed at baseline, week 4, 8, 12, 26 and 52.

    • Manual Muscle Testing (MMT): sum score of 12 proximal+distal and 2 axial muscle groups. Score 0 - 260 (no muscle weakness). 0 = zero contractions in muscle, 10 = normal On a total of 6 CSM

  7. Core set measures (CSM) - Health Assessment Questionnaire (HAQ)

    Time frame: CSMs will be assessed at baseline, week 4, 8, 12, 26 and 52.

    • Health Assessment Questionnaire (HAQ): average of a survey scoring 8 domains, from 0 (without any difficulty) to 3 (unable to do) On a total of 6 CSM

  8. Core set measures (CSM) - Serum muscle enzyme activities

    Time frame: CSMs will be assessed at baseline, week 4, 8, 12, 26 and 52.

    • Serum muscle enzyme activities expressed as the most abnormal one in the upper limit of normal.

    On a total of 6 CSM

  9. Core set measures (CSM) - Extramuscular disease activity

    Time frame: CSMs will be assessed at baseline, week 4, 8, 12, 26 and 52.

    • Extramuscular disease activity on a 10 cm VAS based on the Myositis Disease Activity Assessment, measuring the degree of disease activity of extra-muscular organ systems. Score is based on a 0 - 4 scale, related to worsening or improvement.

    On a total of 6 CSM

  10. Patient-Reported Outcome Measures (PROMs) questionnaire - Fatigue

    Time frame: At baseline, and after 4, 8, 12, 26 and 52 weeks.

    These PROMs relate to different aspects of quality of life, this questionnaire specified on fatigue. The three PROMs are offered as Short Forms: fixed set of 4-10 questions for one of each domain.

    Each item is scored on a 5-point Likert scale, with higher scores indicating better functioning, and item category responses range from 1 to 5.

    For example: 1= not at al, 2 = a little, 3 = moderately, 4 = mostly, 5= completely.

  11. Patient-Reported Outcome Measures (PROMs) questionnaire - Pain interference

    Time frame: At baseline, and after 4, 8, 12, 26 and 52 weeks.

    These PROMs relate to different aspects of quality of life, this questionnaire specified on pain interference (in life). The three PROMs are offered as Short Forms: fixed set of 4-10 questions for one of each domain.

    Each item is scored on a 5-point Likert scale, with higher scores indicating better functioning, and item category responses range from 1 to 5.

    For example: 1= not at al, 2 = a little, 3 = moderately, 4 = mostly, 5= completely.

  12. Patient-Reported Outcome Measures (PROMs) questionnaire - Physical function

    Time frame: At baseline, and after 4, 8, 12, 26 and 52 weeks.

    These PROMs relate to different aspects of quality of life, this questionnaire specified on physical function. The three PROMs are offered as Short Forms: fixed set of 4-10 questions for one of each domain.

    Each item is scored on a 5-point Likert scale, with higher scores indicating better functioning, and item category responses range from 1 to 5.

    For example: 1= not at al, 2 = a little, 3 = moderately, 4 = mostly, 5= completely.

  13. Fatigue

    Time frame: At baseline, and after 4, 8, 12, 26 and 52 weeks.

    The second most important domain according to patients with myositis and health-care providers (OMERACT study group). We will use the Checklist Individual Strength (CIS)-fatigue, a generic fatigue scale, which has been validated in neuromuscular disorders.

  14. Health related quality of life (HR-QoL)

    Time frame: At baseline, and after 4, 8, 12, 26 and 52 weeks.

    HR-QoL will be assessed with EuroQol Group Health Questionnaire (EQ5D). EQ5D is a widely used questionnaire for assessment of general health and has shown responsivity in our previous study on monotherapy IVIg in IIM

  15. Physical activity

    Time frame: Two consecutive weeks, at baseline, week 4, week 8 and week 26.

    Accelerometry will be used to measure physical activity, patients will be offered a wrist-worn wearable (Actigraph GT9X32). For accelerometry we will calculate the mean number of steps and the mean number of flights of stairs per 24 hours, during the 5 most active days per week.

  16. Mean daily prednisone dosage

    Time frame: Calculated at week 4, 8, 12, 26 and 52.

    Start dosage 1 mg/kg (maximum 80 mg). A standard tapering scheme in the first months consists of 10 mg reduction of dosage every 4 weeks.

  17. MRI abnormalities

    Time frame: At baseline, and after 12 and 26 weeks.

    Indicative for edema (T2/STIR) and fatty infiltration (T1) on total body MRI. The MRI results will be used as a marker of inflammation and disease damage, respectively. Sum scores of semi-quantitatively rated muscle, fascial and subcutaneous edema and fatty infiltration will be calculated.

  18. IgG blood levels.

    Time frame: Obtained immediately before, immediately after and two weeks after the administration of study medication

    Immunoglobulin G (IgG) levels in serum samples will be measured by turbidimetry.

  19. Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI).

    Time frame: At baseline, and after 4, 8, 12, 26 and 52 weeks.

    In the subgroup of patients with dermatomyositis, this validated tool will be used to characterize cutaneous dermatomyositis severity and detect improvement in disease activity.

  20. Composite questionnaire on health care use and productivity loss.

    Time frame: At baseline and week 12

    This questionnaire is based on the Medical Consumption Questionnaire (iMCQ) and the Productivity Cost Questionnaire (iPCQ) and is currently being used in the OPTIC trial (add-on prednisone in chronic inflammatory demyelinating polyneuropathy (CIDP)).

  21. Interferon pathway markers

    Time frame: Examined at week 0, 4, 8, 12, 26 and 52.

    Serological biomarkers galectin-9, CXCL10, Siglec-1 are indicative of the interferon pathway and will be measured at week 0, 4, 8, 12, 26 and 52.

Sponsors and collaborators

Lead sponsor

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Other

Collaborators

  • Princess Beatrix Muscle Foundation
  • Prothya Biosolutions

Registry information

Official study title

Treatment With add-on IVIg in Myositis Early In the diSease Course May be sUperior to Steroids Alone for Reaching CLinical improvemEnt

Acronym: TIMEISMUSCLE

Important dates

Study start
2021
Primary completion
2025
Study completion
2026
First posted
Apr 27, 2023
Registry last updated
Feb 27, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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