Treatment with add-on IVIg in Myositis Early In the diSease course May be sUperior to Steroids alone for reaching CLinical improvEment (TIME IS MUSCLE): study protocol of a phase-2 double-blind placebo-controlled randomised trial

Abstract

Introduction

For idiopathic inflammatory myopathies (IIM) (‘myositis’) standard initial treatment is high-dosed glucocorticoids, which results in relatively slow improvement of muscle strength. Early immunosuppression or modulation by intensive treatment (‘hit-early, hit-hard’) may induce faster reduction of disease activity and prevent chronic disability due to disease-induced structural muscle damage. Intravenous immunoglobulin (IVIg) in addition to standard glucocorticoid treatment may be promising in this regard as was shown in various studies: add-on IVIg improved symptoms and muscle strength in refractory myositis patients and monotherapy IVIg improved outcomes after 9 weeks, in about half of treatment-naive patients.

Hypothesis

We hypothesise that early add-on IVIg leads to a greater clinical response after 12 weeks in patients with newly diagnosed myositis, in comparison to prednisone monotherapy. Second, we expect that early treatment with add-on IVIg leads to a faster time to improvement and sustained positive effects on multiple secondary outcomes.

Methods

The Time Is Muscle trial is a phase-2 double-blind placebo-controlled randomised trial. Forty-eight patients with IIM will be treated with IVIg or placebo at baseline (within 1 week after diagnosis) and after 4 and 8 weeks, in addition to standard therapy with prednisone. The primary outcome is the Total Improvement Score (TIS) of the myositis response criteria at 12 weeks. At baseline, and after 4, 8, 12, 26 and 52 weeks, relevant secondary outcomes will be assessed, including time to moderate improvement (TIS≥40), mean daily prednisone dosage, physical activity, health-related quality of life, fatigue and MRI muscle imaging parameters.

Ethics and dissemination

Ethical approval was obtained from the medical ethics committee of the Academic Medical Centre, University of Amsterdam, the Netherlands (2020_180; including a first amendment approval at the 12 April 2023; A2020_180_0001). The results will be distributed through conference presentations and peer-reviewed publications.

Trial registration number

EU Clinical trials register (2020-001710-37).

Correspondence to Renske G Kamperman; [email protected]

STRENGTHS AND LIMITATIONS OF THIS STUDY

• First double-blind placebo-controlled randomised trial in patients with newly diagnosed myositis aiming to provide evidence for an early effect of intravenous immunoglobulin in addition to standard treatment with glucocorticoids.

• Multiple secondary outcomes, including disease activity, physical functioning, fatigue and quality of life will be assessed at multiple time points (up to 52 weeks). This (relatively) long follow-up period can provide valuable information about the sustained effects.

• Study power will be insufficient for reliable estimates of effects in idiopathic inflammatory myopathies subgroups.

Introduction

Idiopathic inflammatory myopathies (IIM), also referred to as ‘myositis’, include dermatomyositis (DM), polymyositis (PM), anti-synthetase syndrome (ASS), immune-mediated necrotising myopathy (IMNM), overlap/non-specific myositis (OM) and inclusion body myositis (IBM). PM is a historical denominator for a clinical syndrome which did not fulfil criteria for DM and IBM; it is now a contested entity within the spectrum and a diagnosis by exclusion.^1–3 IIM is considered treatable, with the exception of IBM which tends to be treatment refractory. Despite immunosuppressant treatment, around 70% of IIM patients have a chronic disease with residual disability and reduced quality of life.^{4 5} This may reflect irreversible tissue damage due to undertreatment in the first treatment phase. Standard treatment of IIM is high-dosed glucocorticoids, for example prednisone, methylprednisolone or dexamethasone, which results in relatively slow improvement of muscle strength. The current treatment strategies of myositis can lead to irreversible tissue damage in some patients, contributing to permanent disability.^{4 6 7} Early immunosuppression by intensive treatment (‘hit-early, hit-hard’) may induce faster reduction of disease activity and prevent chronic disability due to tissue damage in inflammatory disorders, such as myositis.⁸ Intravenous immunoglobulin (IVIg) in addition to standard treatment with glucocorticoids may be promising in this regard: add-on IVIg improved symptoms and muscle strength in patients with steroid refractory resistant DM.^9–13 Patients with immune-mediated necrotising myopathy have been successfully treated with monotherapy IVIg, although the number of reported patients is small.^{14 15} The effect of IVIg in PM is less clear.^{16 17} Our recently published pilot study on treatment-naive patients with IIM (all subtypes, IBM excluded) showed clinically relevant improvement in 45% of patients after six to 9 weeks of first-line IVIg monotherapy. Clinically relevant improvement was defined as at least 40 points on the International Myositis Assessment and Clinical Trial Group Total Improvement Score (IMACS) Total Improvement Score (TIS).¹⁸

Based on a comparison of TIS data from the IMMEDIATE (intravenous IVIg as first-line treatment in idiopathic inflammatory myopathies) study and a series of 11 IIM patients treated with monotherapy steroids in our clinic (unpublished data), IVIg may act faster than high-dosed glucocorticoids. The combination could, therefore, lead to an early and possibly sustained suppression of the inflammatory process when administered together. Previous randomised clinical trials in other immune-mediated disorders have shown the efficacy and safety of the combination of IVIg and prednisone.^19–21 Although the beneficial effect of add-on IVIg has been shown in refractory DM patients who were treated with low or intermediate doses of corticosteroids, it is conceivable but currently unknown whether IVIg in the earliest treatment phase, in addition to high-dosed corticosteroids, is safe and effective compared with high-dosed corticosteroids alone in IIM. We aim to investigate the effect of add-on IVIg to corticosteroids in patients with newly diagnosed IIM.

Aim

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 with 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 (HR-QoL), physical activity and fatigue, and a sustained reduction of muscle MRI abnormalities, as assessed up to 52 weeks.

Methods and analysis

Study status

Recruitment of study participants started on 6 September 2021. First patient was included on 13 September 2021. As of 16 March 2023, 17 patients have been included. This trial has been registered in the Netherlands Trial Registry (NL73727—this registry is not available anymore; data are available through the International Clinical Trial Registry Platform (ICTRP; ICTRP Search Portal (who.int)) and in the EU Clinical trials register (2020-001710-37).

Study procedures

An overview of the study procedures can be found in online supplemental table 1.

Patient and public involvement

The study design and a selection of outcome measures have been discussed during a live meeting with five patients of the myositis workgroup of the Dutch Patient Federation for Neuromuscular Disorders. For example, our choice to use the EQ-5D-5L as measure of quality of life was supported by the patients (which preferred this measure above two other measures).

Following a presentation on accelerometers the patients unanimously shared their preference for a wrist-worn watch opposed to ankle-worn or waist-worn accelerometers. The choice of disease specific patient-reported outcome measures (PROMs) has been discussed with a patient representative, who in turn, is involved in the development of PROMs related to fatigue, pain and physical functioning in myositis.²²

Study design

This study is an investigator-initiated phase-2 double-blind placebo-controlled randomised trial. The study procedures are presented in online supplemental table 1. Patients will be treated with IVIg (2 g/kg body weight; administered over 2–3 days (with a maximum of 80 g/day and a total of 180 g) or placebo (sodium chloride 0.9% intravenous infusion). The study medication is administered at baseline and after 4 and 8 weeks. All patients will start with prednisone 1 mg/kg, with a maximum of 80 mg/day. The standard tapering scheme for the first 3 months consists of 10 mg dose-reduction every 4 weeks. After 12 weeks an alternative, faster tapering scheme may be chosen based on the clinical response, defined as a TIS≥60 points, which marks a major improvement.^{23 24} Tapering schedule after 12 weeks will be at discretion of treating physician.

Study population

This is a single-centre study performed at the Amsterdam University Medical Center, location Academic Medical Centre. The Amsterdam UMC serves as a tertiary referral centre for IIM in the Netherlands and is a coordinating centre of the Dutch Myositis Network, a collaboration between myositis centres in the Netherlands. Since the IMMEDIATE study and the ongoing ADAPT (optimisAtion of Diagnostic Accuracy in idioPathic inflammaTory myopathies) study, the Amsterdam UMC receives between two and three referrals for a suspected myositis per month, from across the Netherlands.^{18 25} We expect to include one or two patients per month. Potentially eligible patients are recruited according to the following inclusion and exclusion criteria.

Inclusion criteria

• Adult patients (≥18 years) with IIM, according to diagnostic criteria:

  • Dermatomyositis.²⁶

  • Anti-syntethase syndrome.²⁷

  • Immune mediated necrotising myopathy.²⁸

  • Overlap/non-specific, including polymyositis.^{1 27}

• Disease duration <12 months (defined as duration of symptoms attributed to myositis before screening).

• Disease activity with a minimum of at least 10% loss on Manual Muscle Testing (MMT) in 13 muscle groups and abnormal scores on two other core set measures (CSMs) of the 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 (eg, 40 mg per day up to 4 days) or intravenous methylprednisolone (eg, 1000 mg daily for 3 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 3 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 (eg, haematological condition, eczema) and is not known for its use in IIM.

  • 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 (ie, bedridden, severe dysphagia requiring a nasogastric tube or symptomatic respiratory muscle weakness (respiratory symptoms in combination with a forced vital capacity below 50% of predicted in upright position)) necessitating more intensive treatment than standard glucocorticoids from the start.

• Signs of severe or rapidly progressive ILD, necessitating respiratory support or progressive ILD on High-resolution computed tomography (HRCT), with ≥10% decrease in vital capacity and/or ≥15% decrease of diffusion.

• A known malignancy, which is likely to interfere with outcome assessment.

• 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 IgA deficiency and IgA serum antibodies.

  • Pregnancy or trying to conceive.

  • Use of loop diuretics.

  • Use of nephrotoxic medication.

• Conditions that are likely to interfere with:

  • Compliance (legally incompetent and/or incapacitated patients are excluded).

  • Evaluation of efficacy (eg, due to severe pre-existing disability as a result of any disease other than myositis or due to a language barrier).

• Immunosuppressive medication or immunomodulatory treatment within the last 3 months (eg, azathioprine, methotrexate, mycophenolate mofetil, tacrolimus, cyclophosphamide, cyclosporine, IVIg, biologicals, Janus kinase inhibitors, plasmapheresis), with evident clinical response (as judged by the treating physician at a screening visit).

Investigational treatment

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 g 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 μg/mL IgA, in a solution of water for injections and glucose. Patients in the control arm will be treated with placebo infusions, containing sodium chloride 0.9%, at baseline and after 4 and 8 weeks.

All patients (intervention arm and control arm) will be treated with 1 mg/kg (maximum 80 mg) daily oral prednisone, which is standard of care.²⁹ A standard tapering scheme in the first 3 months (12 weeks) consists of 10 mg reduction of dosage every 4 weeks. After 12 weeks an alternative, faster scheme can be chosen at discretion of treating physician on the basis of a clinical response, defined as a TIS score ≥60 points which marks a major improvement.^{23 24} If so, prednisone can be tapered by 20%–25% of the existing dose monthly with the goal of achieving a low daily dose of prednisone of approximately 5–10 mg daily within 6 months.²⁴ After 12 weeks, a disease-modifying anti-rheumatic drug (DMARD, eg, methotrexate) will be started in all patients, which is standard of care, except in those patients who are in near-complete or complete remission, as judged by the treating physician. The prescription of a second line immunosuppressant for extramuscular activity (ie, rapidly progressive interstitial lung disease) within 12 weeks is left to the judgement of treating physicians.

Setting

Patients will be informed and enrolled at the inpatient and/or outpatient clinic and will confirm their participation by signing an informed consent form. The first infusion (30 g IVIg or placebo) will be administered at the ward, within 1 week after diagnosis. Patients will be monitored during the first infusion and for the first hours afterwards, in order to detect potential adverse signs. Remaining infusions of the first treatment cycle and the complete second and third treatment cycles will be performed, if possible, at home by experienced home care nurses. A window of 5 days is accepted between the first infusion and the infusion of the remaining study medication. The same window of 5 days is applied for the second and third infusions. In case a patient is already admitted to a hospital at the time of diagnosis, the patient will receive all study medication of the first cycle at the ward at the Amsterdam UMC.

Randomisation and blinding

After informed consent, patients will randomly be allocated to IVIg or placebo treatment. The randomisation procedure is web-based (Castor EDC³⁰). Patients are randomly assigned in a 1:1 ratio, using a block randomisation with random permuted blocks of sizes 4, 6 or 8. Randomisation is stratified according to the subtype of myositis. The randomisation code and treatment allocations will be provided by CASTOR EDC to the trial pharmacist. The trial pharmacist will prepare the study medication. Blinded infusion bags, drip chambers and closure systems, will be used to ensure adequate blinding. Because of the necessity to prepare the investigational medicinal product on-site, treating home care nurses are not blinded. Treating home care nurses will be instructed accordingly to prevent unmasking of patients. The trial pharmacist can only be asked to disclose the allocation of patients in case patients reach an early endpoint, to enable further treatment decisions. If the treatment allocation is disclosed to the treating physician at or after week 26, another, blinded physician will perform the follow-up assessments.

Early endpoint

The treating physician and investigator can decide to withdraw a subject from the study for urgent medical reasons, significant deterioration or insufficient response. The subject will then reach an early endpoint.

Significant deterioration is judged by the treating physician and is defined by the IMACS group as³¹:

• Worsening of physician global activity assessment of ≥2 cm on a 10 cm Visual Analogue Scale (VAS) and a worsening of the MMT by ≥20%.

• Extramuscular organ disease activity worsening by ≥2 cm on a 10 cm VAS.

• A decrease of ≥30% in 3 out of 6 IMACS CSMs.

Insufficient response is defined as a TIS<20: no to minimal improvement³¹ by week 8.

The trial pharmacist will be asked to reveal treatment allocation of patients reaching an early endpoint to the treating physician, if it is deemed necessary for further treatment. The patients who reach an early endpoint will be treated according to standard of care, outside the context of the study (eg, with open-label IVIg). The patients will undergo an end of study assessment and will be followed up.

Patients who reach an early endpoint due to urgent medical reasons (not significant deterioration or insufficient response), will be replaced within the trial.

In case of an underlying malignancy being diagnosed within the study period (up to 52 weeks), the possibility to remain in the study will depend on the possibility of a valid assessment of the primary outcome.

Outcomes

Primary outcome

The primary outcome is the 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. TIS is based on 6 validated CSMs, which each determine disease activity as defined by the IMACS group.³² The six CSMs are: physician global activity assessment, patient global activity assessment, MMT, Health Assessment Questionnaire, muscle enzyme levels and extramuscular disease activity based on the Myositis Disease Activity Assessment Tool.³³ TIS ranges between 0 and 100 and corresponds to a degree of improvement; higher scores correspond to a greater degree of improvement. Cut-offs are based on clinical criteria of the American College of Rheumatology/European League Against Rheumatism: minimal, moderate and major improvement have been defined as TIS ≥20; ≥ 40 and ≥ 60 points, respectively.³²

Secondary outcomes

• Time to response: This is defined as the time to reach a TIS≥40 points, corresponding to moderate improvement, examined at week 4, 8, 12, 26 and 52 weeks.

• Each of the CSMs out of which IMACS TIS is composed. CSMs will be assessed at baseline, and after 4, 8, 12, 26 and 52 weeks.

• Patient-reported outcomes across multiple domains: Three PROMs of the Patient Reported Outcomes Measurement Information System will be used.²² These PROMs relate to different aspects of quality of life and are currently being validated in patients with myositis: fatigue, pain interference and physical function. The PROMs will be assessed at baseline, and after 4, 8, 12, 26 and 52 weeks.

• Fatigue: Fatigue is the second most important domain according to patients with myositis and healthcare providers (OMERACT study group).²² In addition to the PROMs described above, we will use the CIS-fatigue, a generic fatigue scale, which has been validated in neuromuscular disorders. In a pilot study, the CIS-fatigue showed face validity in five patients with IIM. Out of a total of 84 IIM patients who were on immunosuppressive treatment in our clinic, 59 (70%) had abnormal scores indicating severe fatigue (>35 points; unpublished pilot-data). The CIS-fatigue will be assessed at baseline, and after 4, 8, 12, 26 and 52 weeks.

• HR-QoL: HR-QoL will be assessed with EuroQol-5 Dimensions-5 Level Group Health Questionnaire (EQ-5D), at baseline and at 4, 8, 12, 26 and 52 weeks. EQ-5D is a widely used questionnaire for assessment of general health in terms of five health dimensions, and has shown responsivity in our previous study on monotherapy IVIg in IIM.^{18 34}

• Physical activity: Accelerometry will be used to measure physical activity. Patients will be offered a wrist-worn wearable (Actigraph GT9X³⁵) for two consecutive weeks, at baseline and at 4, 8 and 26 weeks. After each period the wearable is collected during a study visit or a regular outpatient visit. For accelerometry, we will calculate the mean number of steps and the mean number of flights of stairs per 24 hours, during the five most active days per week.³⁶

• Mean daily prednisone dosage (per patient; based on prescription and actively questioned use). Calculated at weeks 4, 8, 12, 26 and 52.

• Muscle abnormalities on MRI: Muscle intensity changes indicative for oedema (T2/STIR) and fatty infiltration (T1) on total body MRI at baseline, and after 12, 26 and 52 weeks. The MRI results will be used as a marker of inflammation and disease damage, respectively.^{37 38} Sum scores of semiquantitatively rated muscle oedema and fatty infiltration will be calculated.³⁹

• IgG blood levels: Total IgG levels in serum samples obtained immediately before, and 2 weeks after the administration of study medication at baseline, week 4 and week 8, will be measured by turbidimetry.⁴⁰

• Cutaneous Dermatomyositis Disease Area and Severity Index⁴¹: In the subgroup of patients with DM, this validated tool will be used to assess cutaneous DM severity at baseline, and at 4, 8, 12, 26 and 52 weeks.

• Medical consumption and productivity: The composite questionnaire on healthcare use and productivity loss will be used to assess medical consumption and productivity costs. This questionnaire is based on the Medical Consumption Questionnaire and the Productivity Cost Questionnaire and is currently being used in the OPTIC trial (add-on prednisone in chronic inflammatory demyelinating polyneuropathy).^{42 43} The questionnaire has been revised for myositis patients for the current study. This secondary outcome will be assessed at baseline, and at 12 and 52 weeks. It will be used for an explorative analysis of the significant costs related to IIM and the intervention the from a societal perspective.

Sample size calculation

Based on our pilot data, we anticipate a mean (SD) difference between the groups of (μ2–μ1=65.0–44.4=) 20.6 (23.1) points on the primary outcome measure (TIS of IMACS, for details see primary outcome section) in favour of the IVIg and prednisone treatment group after 12 weeks.¹⁸ This magnitude of effect has been considered to be clinically relevant in add-on studies: with 20 or more extra points on the TIS, a considerable proportion of patients will shift categories from minimal to moderate, or moderate to major improvement. A TIS>20 points is defined as ‘at least minimal clinical improvement’.³² We calculated that enrolment of 21 patients in each group would provide the trial with 80% power to detect a difference in the mean TIS score of 20.6 using a Student’s t-test at a two-sided significance level of 0.05 (PASS V.15 Power Analysis and Sample Size Software, NCSS, ncss.com/software/pass; 2017). Because we assume a drop-out rate of 10 %, we plan to include 24 patients in each group.

Statistical analysis

All data will be analysed according to the intention-to-treat principle. Discrete variables will be summarised by frequencies and percentages. Normally distributed continuous variables will be expressed as means and SDs; non-normally distributed data and ordinal data as medians and IQR (IQR: 25th–75th percentiles). Differences in means of normally distributed continuous variables will be analysed using analysis of variance (ANOVA) with regard to primary outcome, and with (generalised) linear regression with regard to secondary outcomes.

Primary outcome

Difference of the mean TIS after 12 weeks between the intervention and control groups will be analysed with a Student’s t-test. Of note, if both groups have equal variances, the t-test is equivalent to a one-way ANOVA. Additionally, the primary outcome will be analysed using two-way ANOVA, including the stratification variable subtype of myositis into the model. This will enable assessment of effect modification by subtype of myositis and a more precise estimation of treatment effect.

The effect of treatment on the median TIS per patient of three time points (weeks 4, 8 and 12) will also be analysed by Student’s t-test and two-way ANOVA. Per-protocol analyses and multiple imputations in case of missing values will be used to evaluate the robustness of the results found.

Secondary outcomes

The secondary outcomes are considered exploratory. We will analyse the following secondary outcome measures to assess differences between the two treatment groups using the appropriate parametric or non-parametric test statistics or within regression models:

• Time to moderate improvement (TIS≥40) up to 52 weeks, using the Kaplan-Meier estimator of survival function and log-rank statistic.

• CSMs, HR-QoL, PROMs and mean prednisone dosage will each be analysed within appropriate (generalised) linear regression models. Choice of link function will be determined by distribution of the response variable, possibly after dichotomisation, and we will consider treatment group and time since baseline as covariates.

• Physical functioning: measures of accelerometry will likewise be analysed according to an appropriate (generalised) linear regression model, with treatment group and time since baseline as covariates, and 24-hour mean number of steps or flights of stairs as response variables, respectively.

• Muscle MRI: difference of the individual sum scores (relative to baseline) of semiquantitatively rated muscle oedema and fatty infiltration will also be analysed according to (generalised) linear regression models, with treatment group and time since baseline as covariates. For these parameters, we will also examine the interaction between time and group.

• Delta IgG levels.

Of note, while analyses of the primary outcome focus on hypothesis testing, analyses of secondary outcomes focus on estimation of effect sizes with confidence bounds, rather than testing for statistical significance. To investigate whether the effect of treatment after 12 weeks is affected by differences in baseline patient characteristics, an ANCOVA will be performed with inclusion of relevant covariates as identified in secondary outcome analyses. Two-sided alpha of 0.05 will be considered to indicate statistical significance, and we will report effect sizes with 95% CIs.

Discussion

The Time Is Muscle study is a phase-2 double-blind placebo-controlled randomised trial in newly diagnosed myositis patients aiming to provide evidence for an effect of IVIg early in the disease course (first 3 months after diagnosis), in addition to standard treatment with prednisone. The trial is designed with IVIg as add-on treatment based on the assumption that IVIg tends to act faster as compared with most other immunosuppressant or immunomodulatory drugs, which could lead to an early and sustained suppression of the inflammatory process when administered together with glucocorticoids. The efficacy and safety of the combination of IVIg and prednisone have been shown in randomised clinical trials in other immune-mediated disorders and in more advanced stages of myositis.^19–21 However, clinical studies examining the effect of add-on IVIg in the early phase of myositis are lacking. Currently, one prospective open label cohort study in Brazil is being performed, examining the effect of intravenous methylprednisolone and/or IVIg, versus monotherapy methylprednisolone at disease onset (ClinicalTrials.gov Identifier: NCT03092180). As far as we know, our study is the first double-blind placebo-controlled randomised trial in myositis aiming to provide evidence for an effect of early given IVIg in addition to standard treatment with prednisone.

The patients participating in this trial are newly diagnosed myositis patients with muscle weakness as the dominant symptom, who are mostly seen in an outpatient setting. However, due to the multiorgan nature of IIMs (in all subtypes except IMNM), other extramuscular features (skin, lung, heart, joints) are frequently encountered, which, for example, can lead to severe myocarditis, or symptomatic respiratory muscle weakness.⁴⁴ Out of these organ manifestations symptomatic interstitial lung disease is most likely to necessitate the prescription of additional immunosuppressant medication within the study period (first 12 weeks). We will perform exploratory subgroup analyses when this occurs in a considerable number of patients.

Prior treatment with immunosuppressive or immunomodulatory treatment is an exclusion criterion. However, in order to increase the external validity of our findings, patients are still eligible for inclusion if there is no clinical evident response to predefined dosages and a short period of treatment. We will perform post hoc subgroup analyses between patients with and without prior treatment with immunosuppressive or immunomodulatory treatment.

It must be taken into consideration that this study has a relatively small sample size and a heterogeneous patient sample. Although results will be applicable to IIM patients as a group; study power will be insufficient for precise estimates of effects within IIM subgroups. However, valuable information on potential differences in outcomes between IIM subgroups will be collected for exploration in further research.

This study is a phase-2 trial which aims at providing evidence for an effect of early started add-on IVIg in a group of newly diagnosed patients with myositis. In case of a positive result, this could lead to a large phase-3, multinational RCT sufficiently powered to detect effects in subgroups of patients (eg, DM, ASS, immune-mediated necrotising myopathy or OM). The information collected in this study will help to design such a phase-3 trial, including assessment of the cost-effectiveness of add-on IVIg in distinct subgroups of patients.

Ethics and dissemination

Ethical approval was obtained from the medical ethics committee of the Academic Medical Centre, University of Amsterdam, the Netherlands (2020_180). A first protocol amendment has been approved the 12 April 2023 (A2020_180_0001) and relates to inclusion and exclusion criteria, randomisation procedure and reaching an early endpoint within the trial; all amendments are described accordingly in relevant sections of the manuscript.

Potentially eligible patients are informed about the study verbally, either in the outpatient clinic, neurology ward or via a telephone or video call. Study information is sent by (e)mail. Written informed consent will be obtained from all participants. The results will be distributed through conference presentations and peer-reviewed publications.

Several authors of this publication are members of the Netherlands Neuromuscular Center (NL-NMD) and the European Reference Network for rare neuromuscular diseases ERN-EURO-NMD.

Ethics statements

Patient consent for publication

Not applicable.

Footnote

Contributors RGK, AJvdK and JR drafted the initial study design. HAWW, CdB, MdV, JCACdK, CV, MM, FE and INvS contributed substantially to the conception of the study. RGK, SWE, JR and AJvdK conducted the study procedures. RGK, JAB and JR drafted the manuscript which was critically revised for important intellectual content by all other authors. All authors read and approved the final manuscript before submission.

Funding This research received a grant by the Dutch Prinses Beatrix Spierfonds, grant number W.OR21-05 and financial sponsoring from Prothya Biosolutions (formerly known as Sanquin). Prothya Biosulotions will sponsor the following activities: activity measurement with smartwatches, METC approval, database management, study monitoring, travel cost patients, IgG level tests and preparation of study medication by AMC Research Pharmacy.

Competing interests RGK, JAB, SWE, HAWW, CdB, JCACdK, CV and MM report no competing interests. MdV is a member of the Data Monitoring Committee of Novartis Pharma AG and chair of the Independent Data Monitoring Committee of Dynacure. FE reports grants from ZonMw (Dutch Governmental Agency) and Prinses Beatrix Spierfonds. He also reports grants from CSL Behring, Kedrion, Terumo BCT and Takeda Pharmaceutical Company. INvS chaired a steering committee for a CSL-Behring study investigating the safety and efficacy of SCIg in CIDP and received departmental honoraria for serving on scientific advisory boards for CSL-Behring and Kedrion. He received departmental research support from The Netherlands Organisation for Scientific Research, and from the Dutch Prinses Beatrix Spierfonds. All lecturing and consulting fees for I.S were donated to the Stichting Klinische Neurologie, a local foundation that supports research in the field of neurological disorders. He served on the editorial board of the Cochrane Neuromuscular Disease Group, was a member of the organising committee of the Inflammatory Neuropathy Consortium (INC), a standing committee of the Peripheral Nerve Society and was a member of the Scientific Board of the Kreuth III meeting on the optimal use of plasma-derived medicinal products, especially coagulation factors and normal immunoglobulins organised under the auspices of the European Directorate for the Quality of Medicines & HealthCare (EDQM). AJvdK received departmental honoraria for serving on a scientific advisory board for ArgenX. JR received departmental research support from the Dutch Prinses Beatrix Spierfonds, Dutch ALS foundation, Sanquin Plasma Products and Top Sector Life Science and Health.

Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details.

Provenance and peer review Not commissioned; externally peer reviewed.

Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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