TIMEISMUSCLE: Add-on Intravenous Immunoglobulins in Early Myositis

Sponsor

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

Overall Status

Recruiting

CT.gov ID

NCT05832034

Collaborator

Princess Beatrix Muscle Foundation (Other)

Enrollment

Location

Arms

35.6

Anticipated Duration (Months)

1.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Inflammatory Myopathy, Idiopathic Dermatomyositis Antisynthetase Syndrome Immune-Mediated Necrotizing Myopathy Polymyositis Myositis	Drug: Immune Globulin Intravenous (Human) Drug: Placebo	Phase 2

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 Design

Study Type:

Interventional

Anticipated Enrollment :

48 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

Home-care nurse preparing study medication will be unblinded. Home-care nurse is not involved in outcome assessment.

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Sep 13, 2021

Anticipated Primary Completion Date :

Feb 1, 2024

Anticipated Study Completion Date :

Sep 1, 2024

Arms and Interventions

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%

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%

Outcome Measures

Primary Outcome Measures

Change in Total Improvement Score (TIS) [Baseline and 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 Outcome Measures

Time to response (TIS>40 points) [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.
Total Improvement Score (IMACS). [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.
Core set measures (CSM) - physician global activity (PhGA) [CSMs will be assessed at baseline, week 4, 8, 12, 26 and 52.]
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
Core set measures (CSM) - patient global activity (PGA) [CSMs will be assessed at baseline, week 4, 8, 12, 26 and 52.]
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
Core set measures (CSM) - Manual Muscle Testing (MMT) [CSMs will be assessed at baseline, week 4, 8, 12, 26 and 52.]
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
Core set measures (CSM) - Health Assessment Questionnaire (HAQ) [CSMs will be assessed at baseline, week 4, 8, 12, 26 and 52.]
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
Core set measures (CSM) - Serum muscle enzyme activities [CSMs will be assessed at baseline, week 4, 8, 12, 26 and 52.]
5. Serum muscle enzyme activities expressed as the most abnormal one in the upper limit of normal. On a total of 6 CSM
Core set measures (CSM) - Extramuscular disease activity [CSMs will be assessed at baseline, week 4, 8, 12, 26 and 52.]
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
Patient-Reported Outcome Measures (PROMs) questionnaire - Fatigue [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.
Patient-Reported Outcome Measures (PROMs) questionnaire - Pain interference [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.
Patient-Reported Outcome Measures (PROMs) questionnaire - Physical function [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.
Fatigue [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.
Health related quality of life (HR-QoL) [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
Physical activity [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.
Mean daily prednisone dosage [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.
Muscle hyperintensities. [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 edema and fatty infiltration will be calculated. For this parameters we will examine the interaction between time and group.
IgG blood levels. [Obtained immediately before, and two weeks after the administration of study medication]
Immunoglobulin G (IgG) levels in serum samples will be measured by turbidimetry.
Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI). [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.
Composite questionnaire on health care use and productivity loss. [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)).

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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) and is not known for its use in idiopathic inflammatory myopathy
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 loop diuretics
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).