Add-on Intravenous Immunoglobulins in Early Myositis (TIMEISMUSCLE)

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Myositis; Dermatomyositis; Polymyositis; Antisynthetase Syndrome; Immune-Mediated Necrotizing Myopathy; Inflammatory Myopathy, Idiopathic
• Intervention / Treatment: Drug: Immune Globulin Intravenous (Human); Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 44
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Netherlands
  • North Holland
    • Amsterdam, North Holland, Netherlands, 1105 AZ
      • Department of Neurology, Amsterdam UMC, location AMC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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).

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Add-on IVIg; Patients in the intervention arm will be treated with Nanogam® in a dosage of 2 g/kg over 2-5 days, with a maximum of 80 g/day and a total of 180 gram at baseline and after 4 and 8 weeks. Nanogam® contains 100 mg/mL normal human immunoglobulin with a purity of at least 95% IgG and a maximum of 12 microgram/mL IgA, in a solution of water for injections and glucose. The first 30 grams are administered in hospital.	Drug: Immune Globulin Intravenous (Human); 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 Comparator: Placebo; Patients in the control arm will be treated with placebo infusions, containing sodium chloride 0.9%, at baseline and after 4 and 8 weeks. The first 30 grams are administered at the neurology ward, after 4 and 8 weeks infusions will be administered at home	Drug: Placebo; Placebo infusions, containing sodium chloride 0.9%, at baseline and after 4 and 8 weeks.; Other Names: Sodium chloride or saline 0.9%

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Total Improvement Score (TIS)	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.	Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to response (TIS>40 points)	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.	Will be examined at week 4, 8, 12, 26 and 52 weeks.
Total Improvement Score (IMACS).	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.	TIS will be assessed at t = 0, and after 4, 8, 12, 26 and 52 weeks
Core set measures (CSM) - physician global activity (PhGA)	1. 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	CSMs will be assessed at baseline, week 4, 8, 12, 26 and 52.
Core set measures (CSM) - patient global activity (PGA)	2. 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	CSMs will be assessed at baseline, week 4, 8, 12, 26 and 52.
Core set measures (CSM) - Manual Muscle Testing (MMT)	3. 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	CSMs will be assessed at baseline, week 4, 8, 12, 26 and 52.
Core set measures (CSM) - Health Assessment Questionnaire (HAQ)	4. 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	CSMs will be assessed at baseline, week 4, 8, 12, 26 and 52.
Core set measures (CSM) - Serum muscle enzyme activities	5. Serum muscle enzyme activities expressed as the most abnormal one in the upper limit of normal. On a total of 6 CSM	CSMs will be assessed at baseline, week 4, 8, 12, 26 and 52.
Core set measures (CSM) - Extramuscular disease activity	6. 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	CSMs will be assessed at baseline, week 4, 8, 12, 26 and 52.
Patient-Reported Outcome Measures (PROMs) questionnaire - Fatigue	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.	At baseline, and after 4, 8, 12, 26 and 52 weeks.
Patient-Reported Outcome Measures (PROMs) questionnaire - Pain interference	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.	At baseline, and after 4, 8, 12, 26 and 52 weeks.
Patient-Reported Outcome Measures (PROMs) questionnaire - Physical function	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.	At baseline, and after 4, 8, 12, 26 and 52 weeks.
Fatigue	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.	At baseline, and after 4, 8, 12, 26 and 52 weeks.
Health related quality of life (HR-QoL)	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	At baseline, and after 4, 8, 12, 26 and 52 weeks.
Physical activity	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.	Two consecutive weeks, at baseline, week 4, week 8 and week 26.
Mean daily prednisone dosage	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.	Calculated at week 4, 8, 12, 26 and 52.
Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI).	In the subgroup of patients with dermatomyositis, this validated tool will be used to characterize cutaneous dermatomyositis severity and detect improvement in disease activity.	At baseline, and after 4, 8, 12, 26 and 52 weeks.
Composite questionnaire on health care use and productivity loss.	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)).	At baseline and week 12
Moderate improvement proportion	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.	Examined at week 12
MRI abnormalities	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.	At baseline, and after 12 and 26 weeks.
IgG blood levels.	Immunoglobulin G (IgG) levels in serum samples will be measured by turbidimetry.	Obtained immediately before, immediately after and two weeks after the administration of study medication
Interferon pathway markers	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.	Examined at week 0, 4, 8, 12, 26 and 52.

Collaborators and Investigators

• Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Collaborators: Princess Beatrix Muscle Foundation; Prothya Biosolutions
• Investigators: Principal Investigator: Raaphorst, MD, PhD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Publications and helpful links

General Publications

• Dalakas MC, Illa I, Dambrosia JM, Soueidan SA, Stein DP, Otero C, Dinsmore ST, McCrosky S. A controlled trial of high-dose intravenous immune globulin infusions as treatment for dermatomyositis. N Engl J Med. 1993 Dec 30;329(27):1993-2000. doi: 10.1056/NEJM199312303292704.
• Aggarwal R, Rider LG, Ruperto N, Bayat N, Erman B, Feldman BM, Oddis CV, Amato AA, Chinoy H, Cooper RG, Dastmalchi M, Fiorentino D, Isenberg D, Katz JD, Mammen A, de Visser M, Ytterberg SR, Lundberg IE, Chung L, Danko K, Garcia-De la Torre I, Song YW, Villa L, Rinaldi M, Rockette H, Lachenbruch PA, Miller FW, Vencovsky J; International Myositis Assessment and Clinical Studies Group and the Paediatric Rheumatology International Trials Organisation. 2016 American College of Rheumatology/European League Against Rheumatism criteria for minimal, moderate, and major clinical response in adult dermatomyositis and polymyositis: An International Myositis Assessment and Clinical Studies Group/Paediatric Rheumatology International Trials Organisation Collaborative Initiative. Ann Rheum Dis. 2017 May;76(5):792-801. doi: 10.1136/annrheumdis-2017-211400.
• Hoogendijk JE, Amato AA, Lecky BR, Choy EH, Lundberg IE, Rose MR, Vencovsky J, de Visser M, Hughes RA. 119th ENMC international workshop: trial design in adult idiopathic inflammatory myopathies, with the exception of inclusion body myositis, 10-12 October 2003, Naarden, The Netherlands. Neuromuscul Disord. 2004 May;14(5):337-45. doi: 10.1016/j.nmd.2004.02.006. No abstract available.
• Mecoli CA, Park JK, Alexanderson H, Regardt M, Needham M, de Groot I, Sarver C, Lundberg IE, Shea B, de Visser M, Song YW, Bingham CO 3rd, Christopher-Stine L. Perceptions of Patients, Caregivers, and Healthcare Providers of Idiopathic Inflammatory Myopathies: An International OMERACT Study. J Rheumatol. 2019 Jan;46(1):106-111. doi: 10.3899/jrheum.180353. Epub 2018 Sep 15.
• Malattia C, Damasio MB, Madeo A, Pistorio A, Providenti A, Pederzoli S, Viola S, Buoncompagni A, Mattiuz C, Beltramo A, Consolaro A, Ravelli A, Ruperto N, Picco P, Magnano GM, Martini A. Whole-body MRI in the assessment of disease activity in juvenile dermatomyositis. Ann Rheum Dis. 2014 Jun;73(6):1083-90. doi: 10.1136/annrheumdis-2012-202915. Epub 2013 May 1.
• Lim J, Eftimov F, Verhamme C, Brusse E, Hoogendijk JE, Saris CGJ, Raaphorst J, De Haan RJ, van Schaik IN, Aronica E, de Visser M, van der Kooi AJ. Intravenous immunoglobulins as first-line treatment in idiopathic inflammatory myopathies: a pilot study. Rheumatology (Oxford). 2021 Apr 6;60(4):1784-1792. doi: 10.1093/rheumatology/keaa459.
• Oddis CV, Aggarwal R. Treatment in myositis. Nat Rev Rheumatol. 2018 May;14(5):279-289. doi: 10.1038/nrrheum.2018.42. Epub 2018 Mar 29.

Study record dates

Study Major Dates

• Study Start (Actual): September 13, 2021
• Primary Completion (Actual): September 25, 2025
• Study Completion (Estimated): July 1, 2026

Study Registration Dates

• First Submitted: February 21, 2022
• First Submitted That Met QC Criteria: April 14, 2023
• First Posted (Actual): April 27, 2023

Study Record Updates

• Last Update Posted (Actual): February 27, 2026
• Last Update Submitted That Met QC Criteria: February 26, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Myositis; Intravenous immunoglobulins; Inflammatory myopathies; Early symptomatic; Total Improvement Score
• Additional Relevant MeSH Terms: Musculoskeletal Diseases; Nervous System Diseases; Muscular Diseases; Neuromuscular Diseases; Connective Tissue Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Dermatomyositis; Polymyositis; Myositis; Antisynthetase syndrome; Amino Acids, Peptides, and Proteins; Proteins; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Inorganic Chemicals; Chlorine Compounds; Immunoglobulin Isotypes; Immunoglobulin G; Sodium Compounds; Chlorides; Hydrochloric Acid; Immunoglobulins, Intravenous; Sodium Chloride
• Other Study ID Numbers: NL74270.018.20

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No