Phase IIb Evaluation of Ruxolitinib in the Treatment of Inclusion Body Myositis: A Randomized, Double-Blind, Placebo-Controlled Study

Trial ID: 2023-507666-32-00
Protocol: APHP220829
Sponsor: Assistance Publique Hopitaux De Paris

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Diseases & Conditions

Inclusion body myositis

Objectives

The primary objective of this study is to evaluate whether **ruxolitinib** may improve the overall locomotor performance of patients with Inclusion Body Myositis (IBM) after a 1-year treatment period. This is clinically relevant as IBM is a progressive muscle disorder characterized by muscle weakness and atrophy, significantly impacting patients' mobility and quality of life. Improving locomotor performance could potentially enhance daily functioning and reduce disease burden.

Secondary objectives include:

Evaluating the safety and tolerance of ruxolitinib in IBM patients.
Assessing the therapeutic efficacy of ruxolitinib on various parameters related to skeletal muscle involvement, including muscle strength, overall muscular status, respiratory ability, swallowing, and the proportion of adipose component in muscle tissue as observed through magnetic resonance imaging (MRI).
Evaluating the impact of ruxolitinib treatment on the quality of life using the Health Assessment Questionnaire without Disability Index (HAQ-DI) and the Duke health profile.
Assessing the quality of the blinding in this trial.

Participants

The clinical trial focuses on participants diagnosed with **Inclusion body Myositis** (IBM), aiming to assess the impact of ruxolitinib on their locomotor performance over a one-year treatment period. The study population includes both male and female subjects, aged 45 years and older, who are not considered part of a vulnerable population. Participants must have a defined diagnosis of IBM, characterized by specific clinical and biopsy criteria, and must be capable of walking for six minutes without assistance from another person, although external assistive devices are permitted. The trial requires effective contraception for fertile women of childbearing age throughout the study duration. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity. Participants were selected based on their ability to meet the inclusion criteria, including informed consent, potentially with assistance from a trusted person.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy of **ruxolitinib** in improving locomotor performance in patients with **Inclusion body Myositis** (IBM) over a 12-month treatment period. This is a phase IIb, randomized, double-blind, placebo-controlled trial. Participants will be randomly assigned to receive either Jakavi 15 mg tablets or a placebo, administered orally. The trial is expected to commence recruitment on September 16, 2024, and conclude by January 30, 2028.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥ 45 years), ability to walk unassisted for six minutes, and a defined diagnosis of IBM. Following the screening, participants will attend regular follow-up visits to monitor safety, tolerance, and therapeutic efficacy, with assessments including muscle strength, overall muscle status, and quality of life. The primary endpoint is an improvement of 60 meters in the distance walked during a six-minute walk test from baseline to month 12. Secondary endpoints include safety and tolerance, therapeutic muscular efficacy, and quality of life assessments.

The expected duration of participant involvement is approximately 12 months, with conditions for early termination including adverse events or withdrawal of consent. The trial will ensure effective contraception for fertile women of childbearing age throughout the study. The study's blinding quality will be assessed using the New Blinding Index. Participants' involvement will be closely monitored to ensure adherence to the protocol and to address any potential issues promptly.

Treatment

The clinical trial involves the administration of **Jakavi 15 mg tablets**, which contain the active substance **ruxolitinib**. Ruxolitinib is a chemical compound, also known by its synonyms INCB018424 and INCB-018424. The pharmaceutical form of the medication is a tablet, and it is intended for **oral use**. The maximum daily dose is 30 mg, with a total maximum dose of 10,965 mg over the course of the treatment. The treatment period is set for 12 months. The medication is manufactured by Novartis Europharm Limited and is identified by the marketing authorization number EU/1/12/773/009. The administration of Jakavi is monitored to ensure compliance with the dosing schedule.

In addition to the experimental medication, a **placebo** is used as a comparator in the study. The placebo is designed to mimic the Jakavi 15 mg tablets in appearance but does not contain any active substance. The placebo is utilized to assess the efficacy of ruxolitinib by providing a control group for comparison. The placebo administration follows the same route and frequency as the experimental medication to maintain consistency in the trial design. Participant compliance with the placebo regimen is also monitored throughout the study period.

Efficacy

The efficacy of the clinical trial titled "BIGTIM: Blocking Interferon-γ by ruxolitinib for Treating Inclusion body Myositis: a phase IIb trial" will be assessed using both primary and secondary endpoints. The primary endpoint is the improvement of 60 meters in the distance walked during a 6-minute walk test (6MWD) from baseline to month 12 (M12). This measure will evaluate the overall locomotor performance of patients with Inclusion Body Myositis (IBM) after a one-year treatment period with **ruxolitinib**.

Secondary endpoints include the safety and tolerance of **ruxolitinib** in IBM patients, assessed through adverse events classified according to the MedDRA classification. Therapeutic muscular efficacy will be evaluated by changes from baseline to M12 in parameters related to skeletal muscle involvement. These parameters include muscle strength, measured by dynamometer for maximal voluntary isometric muscle strength (Nm) in hand grip, knee extension and flexion, and elbow flexion and extension. Overall muscle status will be assessed using the 6MWD, IBM Weakness Composite Index (IBMWCI), and IBM Functional Rating Scale (IBMFRS), along with CK level measurement for myonecrosis. Additionally, improvement or stability in quality of life will be assessed between baseline and M12 using the Health Assessment Questionnaire without Disability Index (HAQ-DI) and the Duke health profile. The quality of the blinding will be evaluated using the New Blinding Index (Bang, 2004).

Inclusion and Exclusion Criteria

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Inclusion Criteria

Age ≥ 45 years
Effective contraception for the duration of the clinical trial for fertile women of childbearing age. The participant agrees to follow the contraceptive requirements detailed in the protocol.
Defined diagnosis of IBM according to data-derived criteria (Llyod et al, 2014): Patient must fulfill the three following criteria for being diagnosed as IBM: (1) finger flexor or quadriceps weakness; and (2) muscle biopsy showing endomysial inflammation; and (3) muscle biopsy showing invasion of nonnecrotic muscle fibers or rimmed vacuoles
To be able to walk 6 min without assistance from another person (external assist devices permitted [e.g., canes, walkers, or rollators])
Patient informed and having signed the consent for participation, possibly assisted by a trusted person

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Exclusion Criteria

Pregnancy or breastfeeding
Patient under guardianship, curatorship, safeguard of justice or deprived of liberty
Patient with cognitive disorders or unable, according to the investigator, to understand the study and/or to give informed consent According to the appreciation of the investigator, non-French speaking patients may be included if a close one is able to translate the information provided. The patient must be able to benefit from the accompaniment of a relative for all of their visits (in teleconsultation and in hospital).
Quadriceps weakness (manual muscle testing, MRC) below or equal 1
Forced vital capacity (FVC) or forced expiratory volume (FEV) < 50% of predicted value
Concomitant use of immunomodulatory drugs including previous treatment with JAK inhibitor, or medications acting on muscle anabolism or catabolism
Live vaccine within the 4 weeks before starting ruxolitinib therapy
Comorbidity or active chronic disease which contraindicate ruxolitinib: • If the results of the biological assessment including blood count, blood formula and biochemistry and dating back less than three months are available, see the non-inclusion criteria below. For patients whose results of the biological assessment carried out on the day of the inclusion and randomization visit are not yet available, these criteria constitute secondary exclusion criteria to be checked upon receipt of the results and before the randomization.  Lipid parameters abnormalities/elevations (in lack of cardiovascular risk factors, normal values with or without lipid-lowering treatment are: CTtotal cholesterol < 2 g/L; LDL-C < 1.6 g/L; HDL-C > 0.4 g/L; TGtriglycerides < 1.5 g/L)  Severe renal impairment (stage 4) and end-stage renal disease (stage 5): GFR < 30mL/min/1.73m2  Hepatic impairment: AST/ALT > 3 ULN and bilirubin > 1.5 ULN  Cytopenia (polymorphonuclear neutrophilsPNN ≤ 1.5 Giga/L or platelets ≤ 75 Giga/L or hemoglobin ≤ 10 g/dL)
Active SARS-CoV-2 infection (patient can be included once infection resolved)
Any medical condition which limits the ability of participant to participate in study
Necessity to use a drug incompatible with ruxolitinib (see 7.4)
Hypersensitivity to the IMP’s active substance (ruxolitinib) or to any of the excipients (Cellulose microcrystalline, magnesium stearate, silica colloidal anhydrous, sodium carboxymethyl starch (Type A), povidone K30, hydroxypropylcellulose 300 to 600 cps, lactose monohydrate)
Non-affiliation to a social security scheme or to another social protection scheme, patient on AME (state medical aid)
Foreseeable inability, according to the investigator, to participate in all the visits, treatments and measures provided for in the protocol
Concomitant participation in another clinical trial on medical product for human use, to a clinical investigation on a medical device, to interventional study involving human participants or in the exclusion period at the end of a previous clinical trial on medical product for human use, a clinical investigation on a medical device, or study involving human participants. Participation in non-interventional research is permitted.