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Tacrolimus Combined With Low-dose Prednisone for Treatment of Myasthenia Gravis

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ClinicalTrials.gov Identifier: NCT04768465
Recruitment Status : Recruiting
First Posted : February 24, 2021
Last Update Posted : February 24, 2021
Sponsor:
Information provided by (Responsible Party):
Da, Yuwei, M.D.

Brief Summary:
This study is designed to evaluate the effectiveness and safety of tacrolimus combined with low-dose prednisone in the management of myasthenia gravis patients, compared to tacrolimus as initial immune monotherapy.

Condition or disease Intervention/treatment
Myasthenia Gravis Drug: Pyridostigmine, Prednisone, Tacrolimus Drug: Pyridostigmine, Tacrolimus

Detailed Description:
This is a single center, observational real-world study recruiting myasthenia gravis patients from Neurology Departments of Xuanwu Hospital, aiming to compare effectiveness and safety of 2 different inmunotherapy for MG. The study plans to recruit 160 MG participants and divides into 2 treatment groups according to physician's judgment and preferences of patients, one is combined immunotherapy group in which tacrolimus added with low-dose prednisone (0.25mg/kg/d), and the other is tacrolimus monotherapy group. Both groups can be treated with pyridostigmine to relieve symptoms. Patients are followed up at 1, 3 and 6 month after treatment initiation to assess the efficacy of both regimen. The primary outcome is the change of MG-ADL scores. Also, liver and renal functions are tested to monitor any side effects. Patients' clinical records are uploaded to an online database.

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Study Type : Observational [Patient Registry]
Estimated Enrollment : 160 participants
Observational Model: Cohort
Time Perspective: Prospective
Target Follow-Up Duration: 6 Months
Official Title: Effectiveness and Safety of Tacrolimus Combined With Low-dose Prednisone for Treatment of Myasthenia Gravis: A Real-world Study
Actual Study Start Date : January 1, 2021
Estimated Primary Completion Date : December 31, 2023
Estimated Study Completion Date : October 31, 2024


Group/Cohort Intervention/treatment
Combined Immunotherapy

MG patients are treated with tacrolimus combined with low-dose prednisone (0.25mg/kg/d).

Symptomatic treatment like pyridostigmine bromide can be added to relieve symptoms (≤480mg/d).

Drug: Pyridostigmine, Prednisone, Tacrolimus
Dose of tacrolimus should be initiated based on CYP3A5*3 polymorphism and adjusted to achieve blood trough concentration of 4.8-10.0 ng/ml. Prednisone is administrated with an initial dose of 0.25mg/kg/d and started to tamper with the achievement of MMS or the presence of any intolerable side effects. The rate of tampering is considered by the physician, usually no more than 5mg/month. If the participants failed to maintain MMS, dose of prednisone should be increased 5mg/week to 0.25mg/kg/d and maintained until MMS reached again. After MMS sustained for 1 month, prednisone dose would be tapered again with 2.5mg/month. Calcium and potassium supplements and gastric mucosa protectors could be addressed to avoid any adverse effects of prednisone. Treatment regimens are determined based on the physician's judgment and preferences of the patients. This study was observational and do not change the clinical course of patients.
Other Names:
  • Pyridostigmine Bromide
  • Deltacortone/Meticorten/Prednisone Acetate Tablets
  • Prograf/FK506

Tacrolimus monotherapy
MG patients are treated with tacrolimus as initial immune monotherapy. Symptomatic treatment like pyridostigmine bromide can be added to relieve symptoms (≤480mg/d).
Drug: Pyridostigmine, Tacrolimus
Dose of tacrolimus should be initiated based on CYP3A5*3 polymorphism and adjusted to achieve blood trough concentration of 4.8-10.0 ng/ml. Treatment regimens are determined based on the physician's judgment and preferences of the patients. This study was observational and do not change the clinical course of patients.
Other Names:
  • Pyridostigmine Bromide
  • Prograf/FK506




Primary Outcome Measures :
  1. Change of MG-specific Activities of Daily Living scale (MG-ADL) from Baseline [ Time Frame: Baseline, 1 month, 3 months, 6 months ]
    The MG-ADL is an 8-item scale to assess symptoms of myasthenia gravis patients obtained by summing the responses to each individual item (Grades: 0,1,2,3). The score ranges from 0 to 24.


Secondary Outcome Measures :
  1. Time to achievement of minimal manifestations (MMS) or better [ Time Frame: From Baseline to 6 months ]
    The time duration from treatment initiation to the achievement of MMS or better. Clinical statuses of patients are assessed and categorized according to Myasthenia Gravis Foundation of America (MGFA) post-intervention status (PIS). MM or better includes Minimal Manifestation (MM), Pharmacologic Remission (PR) or Complete Remission (CR).

  2. Time to achievement of Patient-Acceptable Symptom States [ Time Frame: From Baseline to 6 months ]
    The Patient-Acceptable Symptom States question is a simple yes or no query that asked: "Considering all the ways you are affected by Myasthenia, if you had to stay in your current state for the next month, would you say that your current disease state status is satisfactory?" This question reflects the patients assessment of their own health.

  3. Change of Quantitative Myasthenia Gravis (QMG) Scores from Baseline [ Time Frame: Baseline, 1 month, 3 months, 6 months ]
    The QMG is a 13-item scale which measures ocular, bulbar, limb function and respiratory function. The total score ranges from 0 (no myasthenic findings) to 39 (maximal myasthenic deficits) obtained by summing the responses to each individual item (None=0, Mild=1, Moderate=2, Severe=3).

  4. Change of Myasthenia Gravis Quantity-of-Life Scale (MG-QoL15) from Baseline [ Time Frame: Baseline, 1 month, 3 months, 6 months ]
    The MG-QOL15 is helpful in informing the clinician about the patient's perception of the extent of and dissatisfaction with myasthenia gravis (MG)-related dysfunction. MG-QOL15 evaluates patients' aspects about physical status, social adaptation and mental well-being.

  5. Changes of MG-ADL subscores from baseline [ Time Frame: Baseline, 1 month, 3 months, 6 months ]
    Subscores of ADL items can reflect patients' assessment about different MG-related dysfunctions, including ptosis, diplopia, talking, chewing, swallowing, breathing and limbs function.

  6. Serum IL-2 level [ Time Frame: Baseline, 1 month, 3 months, 6 months ]
    Tacrolimus exerts its immunosuppressive effect by inhibiting the early phase gene expression during T-cell activation, including the pro-inflammation IL-2 gene. Thus serum IL-2 is tested as a target of tacrolimus and also a marker of in vivo auto-immune status after treatment.

  7. Treatment Failure [ Time Frame: Baseline to 6 months ]
    Treatment failure is defined as discontinuation of tacrolimus therapy in patients who failed to achieve MMS or better or suffered from exacerbations (MG-ADL or QMG scores increase 50%) or myasthenia crisis.

  8. Withdrawal [ Time Frame: Baseline to 6 months ]
    Participants quit the clinical trial for any reason including unsatisfied response, economic burden or poor compliance to treatment protocol. Patients may quit at any time they want.


Biospecimen Retention:   Samples With DNA
Blood samples are collected at baseline and 1, 3, 6 months after treatment initiation to monitor side effect and serum IL-2 level.


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Patients with Myasthenia Gravis
Criteria

Inclusion Criteria:

  • Age ≥18
  • Clinical Diagnosis of MG is confirmed based on typical clinical features of fluctuating muscle weakness, with at least 1 of the following supporting evidence:

    1. positive clinical response to acetylcholinesterase inhibitor
    2. positive AchR-Ab or MuSK-Ab testing
    3. decrement >10% in repetitive nerve stimulations study (RNS) or increased jitter on single-fibre electromyography (SFEMG)
  • MGFA clinical classification: I - IV
  • Baseline MG-ADL ≥ 3
  • Disease course from onset to enrollment ≤ 12 months
  • Cooperation to followup
  • Written informed consent

Exclusion Criteria:

  • Initiation of immunosuppressant for MG prior to screening, including Prednisone, Methylprednisolone, Azathioprine, Methotrexate, Cyclosporine A, Mycophenolate Mofetil, Tacrolimus and Cyclophosphamide
  • Treatment of immunosuppressant for other concomitant disease 6 months prior to recruitment
  • Rapid immunosuppressive treatments like Intravenous immunoglobulin or plasma exchange 1 month prior to recruitment
  • Thymectomy within 3 months prior to Screening
  • Concomitant chronic degenerative, psychiatric, or neurologic disorder that can cause weakness or fatigue
  • Consciousness, dementia or schizophrenia
  • Pregnancy or lactation, unwillingness to avoid pregnancy
  • Uncontrolled hypertension or diabetes, Liver or kidney dysfunction, Cataract, Severe osteoporosis, Femoral head necrosis; Hyperkalemia, HIV, Acute or chronic infection
  • Other conditions that would preclude participation

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04768465


Contacts
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Contact: Yuwei Da, M.D. 00-86-010-83198493 dayuwei1000@163.com
Contact: Yuwei Da, M.D. 00-86-010-83198493 dayuwei100@hotmail.com

Locations
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China, Beijing
Yuwei Da Recruiting
Beijing, Beijing, China, 100053
Contact: Yuwei Da, M.D.    00-86-010-83198492    dayuwei1000@163.com   
Sponsors and Collaborators
Da, Yuwei, M.D.
Investigators
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Study Chair: Yuwei Da, M.D. Xuanwu Hospital, Beijing
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Responsible Party: Da, Yuwei, M.D.
ClinicalTrials.gov Identifier: NCT04768465    
Other Study ID Numbers: 1.0
First Posted: February 24, 2021    Key Record Dates
Last Update Posted: February 24, 2021
Last Verified: February 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Da, Yuwei, M.D.:
myasthenia gravis
treatment
tacrolimus
low-dose prednisone
Additional relevant MeSH terms:
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Myasthenia Gravis
Muscle Weakness
Muscular Diseases
Musculoskeletal Diseases
Neuromuscular Manifestations
Neurologic Manifestations
Nervous System Diseases
Pathologic Processes
Paraneoplastic Syndromes, Nervous System
Nervous System Neoplasms
Neoplasms by Site
Neoplasms
Paraneoplastic Syndromes
Autoimmune Diseases of the Nervous System
Neurodegenerative Diseases
Neuromuscular Junction Diseases
Neuromuscular Diseases
Autoimmune Diseases
Immune System Diseases
Prednisone
Bromides
Tacrolimus
Pyridostigmine Bromide
Anti-Inflammatory Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents