An RCT of Mycophenolate Mofetil (MMF) in Fibrotic Hypersensitivity Pneumonitis (MYCOHYPE)

Mycophenolate Mofetil and Prednisolone Versus Prednisolone Alone in Fibrotic Hypersensitivity Pneumonitis: a Randomized Controlled Trial

To our knowledge, there is no randomized controlled trial assessing the efficacy of mycophenolate mofetil (MMF) in the treatment of HP. We aim to perform a randomized study to assess the efficacy and safety of a regimen consisting of MMF and prednisolone against a regimen consisting of prednisolone alone for treating fibrotic HP. We hypothesize that the treatment of patients with fibrotic HP with MMF and prednisolone will be more effective and safer than treatment with prednisolone alone.

Study Overview

• Status: Recruiting
• Conditions: Hypersensitivity Pneumonitis
• Intervention / Treatment: Drug: Prednisolone; Drug: Mycophenolate Mofetil plus prednisolone

Detailed Description

Hypersensitivity pneumonitis (HP) is a complex immunologically-mediated interstitial lung disease (ILD) resulting from sensitization to an inhaled antigen. It may be categorized into acute (acute/subacute) or chronic forms based on the duration of disease or evidence of chronicity on radiological or pathological findings. Lately, the American Thoracic Society (ATS) Guidelines 2020 has endorsed a new classification of HP into non-fibrotic and fibrotic types based on the absence or presence of signs of fibrosis on chest computed tomography (CT) or histology. According to a survey study, about three-fourths of respiratory physicians believe that fibrotic HP should be treated with glucocorticoids as the treatment of first choice, which also reflects the practice in most centers worldwide. However, there is some evidence that glucocorticoids may not be effective in the long-term treatment of fibrotic HP. Also, glucocorticoids are associated with several adverse effects especially when used over a long duration. Therefore, most experts recommend that glucocorticoids should be tapered to the lowest possible dose after a trial of about three months in chronic/fibrotic HP.

Hypersensitivity pneumonitis is characterized by an exaggerated T cell-mediated immune inflammatory response (T-lymphocytic alveolitis) due to increased migration, local proliferation, and decreased programmed cell death of lymphocytes. Mycophenolate mofetil (MMF) is an immunosuppressive drug that acts by inhibiting the proliferation of T-lymphocytes and suppressing the recruitment of lymphocytes and monocytes into the sites of inflammation. Therefore, MMF is likely to be effective in the treatment of HP. There are only a few retrospective studies on the efficacy of MMF in the treatment of HP. To our knowledge, there is no randomized controlled trial assessing the efficacy of MMF in the treatment of HP.

We aim to perform a randomized study to assess the efficacy and safety of a regimen consisting of MMF and prednisolone against a regimen consisting of prednisolone alone for treating fibrotic HP. We hypothesize that the treatment of patients with fibrotic HP with MMF and prednisolone will be more effective and safer than treatment with prednisolone alone.

• Study Type: Interventional
• Enrollment (Anticipated): 144
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Sahajal Dhooria, MD, DM; Phone Number: +911722756827; Email: sahajal@gmail.com
• Study Contact Backup: Name: Ritesh Agarwal, MD, DM; Phone Number: +911722756825; Email: agarwal.ritesh@outlook.in

Study Locations

• India
  • Chandigarh, India, 160012
    • Recruiting
    • Postgraduate Institute of Medical Education and Research
    • Contact: Sahajal Dhooria, MD, DM; Phone Number: +911722756827; Email: sahajal@gmail.com
    • Contact: Ritesh Agarwal, MD, DM; Phone Number: +911722756825; Email: agarwal.ritesh@outlook.in

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

i. A diagnosis of fibrotic hypersensitivity pneumonitis according to the criteria proposed in the American Thoracic Society Guideline 2020 ii. Screening FVC at least 40% of the predicted value iii. Able to provide a written, informed consent for participation in the trial

Exclusion Criteria:

i. Baseline FVC <40% predicted ii. Leucopenia (white blood cell count <4·0 × 10^9 per L), significant thrombocytopenia (platelet count <100 × 10^9 per L), or clinically significant anemia (hemoglobin <10 g/dL) iii. Baseline liver transaminases (alanine aminotransferase and aspartate aminotransferase) or bilirubin more than 1·5 times the upper normal limit (except in the case of Gilbert's syndrome) iv. Serum creatinine higher than 2.0 mg/dL v. Uncontrolled congestive heart failure vi. Receipt of prednisolone (more than or equal to 10 mg/day, or equivalent), in the 4 weeks before randomization vii. Prior use of prednisolone (more than or equal to 10 mg/day, or equivalent), MMF, azathioprine, cyclophosphamide, cyclosporine or any other non-glucocorticoid immunosuppressant drug, or antifibrotic agents for more than 12 weeks in the previous year viii. Active infection (lung or elsewhere) whose management would be compromised by MMF or prednisolone ix. Other serious concomitant medical illness (eg, cancer), chronic debilitating illness (other than chronic HP), or drug abuse x. Pregnancy (documented by urine pregnancy test) or breastfeeding xi. Unwilling to participate in the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Prednisolone alone; Oral prednisolone will be administered over 52 weeks, according to following schedule 0.75 mg/kg x 2 weeks 0.5 mg/kg x 2 weeks 20 mg/day x 4 weeks 15 mg/day x 4 weeks 10 mg/day x 4 weeks 5 mg/day x 10 weeks 5 mg on alternate days x 26 weeks	Drug: Prednisolone; Prednisolone is a glucocorticoid that suppresses inflammation by several mechanisms.; Other Names: Control
Experimental: Mycophenolate mofetil plus prednisolone; Oral prednisolone will be administered according to the schedule in the prednisolone alone arm. Mycophenolate mofetil will be administered starting from 2 weeks after randomization. It will be initiated at a dose of 500 mg twice daily and will be escalated to 1000 mg twice daily after two weeks.	Drug: Mycophenolate Mofetil plus prednisolone; Prednisolone is a glucocorticoid that suppresses inflammation by several mechanisms. Mycophenolate mofetil (MMF) is an immunosuppressive drug that acts by inhibiting the proliferation of T-lymphocytes and suppressing the recruitment of lymphocytes and monocytes into the sites of inflammation.; Other Names: Intervention

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Lung function (FVC) decline	Annual rate of decline in forced vital capacity (FVC) assessed using spirometry assessed over 52 weeks	52 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
FEV1 decline	Annual rate of decline in forced expiratory volume in one second (FEV1) assessed using spirometry over 52 weeks	52 weeks
Severity of breathlessness	Severity of dyspnea as assessed using the modified Medical Research Council (mMRC) scale	52 weeks
Six-minute walk distance	Change in six-minute walk distance (6MWD) from the baseline that will be performed using American Thoracic Society guidelines	52 weeks
Disease specific health status	Interstitial lung disease (ILD)-specific health status as assessed by the King's Brief ILD Questionnaire	52 weeks
Diffusion capacity	Change in the diffusion capacity for carbon monoxide (DLCO) of the lung from the baseline	52 weeks
Proportion of subjects who develop progressive pulmonary fibrosis (PPF)	Proportion of subjects who develop progressive pulmonary fibrosis (PPF), which will be defined using the American Thoracic Society 2022 recommendations	52 weeks
Proportion of subjects who develop acute exacerbation(s)	Proportion of subjects who develop acute exacerbation(s), which will be defined using the definition proposed by the International Working Group in 2016	52 weeks
Treatment-emergent adverse effects	Number of treatment-related adverse effects in each arm. The grading of adverse events according to the Common Terminology Criteria for Adverse Events version 5.0	52 weeks

Collaborators and Investigators

• Sponsor: Postgraduate Institute of Medical Education and Research
• Investigators: Principal Investigator: Sahajal Dhooria, MD, DM, Postgraduate Institute of Medical Education and Research, Chandigarh, India

Study record dates

Study Major Dates

• Study Start (Actual): November 23, 2022
• Primary Completion (Anticipated): September 23, 2025
• Study Completion (Anticipated): October 23, 2025

Study Registration Dates

• First Submitted: November 15, 2022
• First Submitted That Met QC Criteria: November 15, 2022
• First Posted (Actual): November 23, 2022

Study Record Updates

• Last Update Posted (Actual): November 30, 2022
• Last Update Submitted That Met QC Criteria: November 29, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: interstitial lung disease; ILD; diffuse parenchymal lung disease; HP
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Respiratory Hypersensitivity; Lung Diseases, Interstitial; Hypersensitivity; Pneumonia; Alveolitis, Extrinsic Allergic; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Neuroprotective Agents; Protective Agents; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antitubercular Agents; Antibiotics, Antitubercular; Prednisolone; Methylprednisolone Acetate; Methylprednisolone; Methylprednisolone Hemisuccinate; Prednisolone acetate; Prednisolone hemisuccinate; Prednisolone phosphate; Mycophenolic Acid
• Other Study ID Numbers: MYCOHYPE

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Individual patient data might be made available on request, after the completion of the study
• IPD Sharing Time Frame: After the completion and publication of the study results
• IPD Sharing Access Criteria: On a reasonable request
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No