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This is a prospective interventional open-label randomized trial. The patients treated with anti-
PD-1 (programmed-death receptor type 1) or anti-PD-L1 (programmed-death ligand) antibodies in case of new acute onset interstitial changes or new seriuos respiratory system related symptoms will be recruited for this study to perform diagnostics. At the recruitment the patient will be randomized 1:1 to investigatory or control arm, the randomization will be stratified upon three criteria:
ARM B - CONTROL GROUP the starting dose will be 1-4mg/kg of body weight of prednisone , depending on clinical condition and pneumonitis severity, the induction treatment will last 5-7 days; in case of severe condition - no improvement after 48-72 h of initial treatment - introduction of immunosuppressive agent is recommended: cyclophosphamide, mofetil mycophenolate or infliximab. A continuation treatment with dose tapering is than planned, starting from oral dose of 30-60mg q 24h of prednisone, and dose reduction of 10mg q 24 h each 1 week. This arm will be treated for 6-12 weeks.
During the treatment and after its termination the function of respiratory system, interstitial changes in radiologic examinations, anticancer response, survival time, pneumonitis relapse and glucocorticosteroid side effects will be monitored and evaluated. The observation will last up to 52 weeks.
Full description
In both groups the diagnostic process will be the same, based upon the existing recommendations it will involve:
detailed medical history and physical examination;
laboratory tests: CBC, CRP, PCT, ALT, AST, CK, LDH, Na, K, Ca, glucose, proteinogram, flow cytometry, IgG and IgM levels, anti-nuclear antibodies (immunofluorescence, dilution), cytomegalovirus (CMV) polymerase-chain reaction (PCR), IgG and IgM for Legionella pneumophila, Chlamydia pneumoniae, Mycoplasma pneumoniae, QuantiferonTB-GOLD, NT- proBNP, troponin T;
arterialized blood gas panel;
in case it was not yet performed - chest computed tomography with contras enhancement with exclusion of pulmonary embolism;
12-lead electrocardiograph
spirometry, full body plethysmography with carbon monoxide diffusion, 6-minute walk test
flexible bronchoscopy with:
culture for aerobic bacteria
culture for Mycobacterium tuberculosis (TB), TB PCR,
culture for funguses, Aspergillus antigen, PCR and immunofluoroscopic examination for Pneumocystis jiroveci (PCP)
bronchoalveolar lavage (BAL) with BAL fluid cell analysis
transbronchial lung biopsy with forceps or nitrogen-criobiopsy, exclusion of CMV pneumonia and neoplasm progression, histological examination for pneumonitis histological pattern; bronchoalveolar lavage and lung biopsy will be performed only in patient with no clinical contradictions.
Interstitial lung diseases related to immune checkpoint inhibitor, i.e. interstitial pneumonia related to checkpoint inhibitor or immunotherapy, i.e. pneumonitis: definition:
the appearance of new radiological changes in chest examination (chest CT or plain radiogram proved with chest CT) after being exposed (treated) with anti-PD-1 or anti-PD-L1 monoclonal antibody, the radiological changes can be described as interstitial: ground glass opacities, consolidations with air bronchogram, interstitial septa thickening, central lobular nodules with perilymphatic distribution; the changes cannot be explained with neoplasm progression, active respiratory infection, heart failure or one of the above is not a sole explanation for the changes. The radiological changes are sometimes accompanied with respiratory system related symptoms. Each case need detailed differential and diagnosis of pneumonitis diagnosis can be made established after active exclusion of other potential causes. Good reaction for glucocorticosteroid treatment makes the diagnosis more likely.
The severity of pneumonitis should be based on 5 point scale based on the modified Common Terminology for Adverse Events (CTC AE) v. 5 criteria:
Grade 1 (G1) Interstitial changes with no symptoms and no progression in follow-up examination after few days.
Grade 2 (G2) Interstitial changes without respiratory failure with mild to moderate respiratory symptoms.
Each case of asymptomatic relapse. Grade 3 (G3) Interstitial changes with acute respiratory failure and the need of oxygen therapy.
Grade 4 (G4) Interstitial changes with acute respiratory failure and the need of mechanical ventilation.
Grade 5 (G5) Death related to acute interstitial pneumonitis.
The diagnostics and treatment of patient should be based on patients condition and conducted in pulmonology or intensive care unit (ICU) department. The treatment should always be driven by the most likely diagnosis and the participation in the study should not delay any procedure or medication administration.
In cases when radiological changes were discovered and severity is grade 1 it is recommended to perform a follow up chest radiograph after 5-7 days to see the dynamics and reassess the severity.
In case of elevated inflammatory markers, clinical, laboratory or microbiological signs of infection accompanying pneumonitis it is recommended to administer antibiotics. Antibiotics will not be routinely used in the whole study population.
Arm A: initial dose in grade 2 is 1 mg/kg of body weight of oral prednisone, in grade 3-4 - 2- 4mg/kg of body weight of intravenous methylprednisolone, depending on severity and clinical condition. Induction treatment for 5-7 days; in cases of severe course - bad condition and no improvement after initial 48-72 h - introduction of cyclophosphamide, mycophenolate mofetile or infliximab.
Arm B: initial dose in grade 2 is 1 mg/kg of body weight of oral prednisone, in grade 3-4 - 2- 4mg/kg of body weight of intravenous methylprednisolone, depending on severity and clinical condition. Induction treatment for 5-7 days; in cases of severe course - bad condition and no improvement after initial 48-72 h - introduction of cyclophosphamide, mycophenolate mofetile or infliximab.
Dosage and administration: Preferred intravenous corticosteroid is methylprednisolone, the dosage range is 1-4 mg/kg of body weight, but in case 4mg/kg is considered a flat dose of 500mg q 24 h is recommended. The medication will be diluted in saline, it will be administered in single daily dose.
The preferred oral medication is prednisone, dosage is 1mg/kg of body weight, but not more than 60mg, administered in single dose daily.
The administration of cyclophosphamide, mycophenolate mofetile or infliximab will be based on case-by-case decision of multidisciplinary board and dosage will be based on the summary of the medical product characteristics.
During glucocorticosteroid therapy no routine prophylaxis of pneumocystis pneumonia is recommended, and the administration of co-trimoxazole should be analyzed case by case; it should be considered in cases of positive PCR results for Pneumocystis jiroveci and in patient with T C4+ cells depletion in flow cytometry - less than 200 cells per microliter. During steroid therapy osteoporosis prophylaxis can be considered. We do not recommend antifungal prophylaxis.
Arm A: The maintenance treatment with oral agent, the general rules must be meet - tapering starts at the dose of 60mg q 24 h of prednisone for 2-4 weeks, the reduction is not faster than 10mg each 14 days, the maintenance dose if flat 10mg q 24 h dose for 8 weeks and the withdraw should be slow over 4 weeks. The treatment should last 12-24 weeks or longer. The detailed dose of daily prednisone is presented in Tables.
Arm B: Treatment with oral agent, based on general rules - the tapering starts at the dose of 30- 60 mg q 24h of prednisone, the reduction is no faster than 10mg each 7 days, the treatment lasts between 6 and 12 weeks. The detailed dosage proposition is presented in the Tables.
Dosage and administration: The preferred oral agent is prednisone, in single daily dose administered in the morning. The recommended dose of co-trimoxazole in case of PCP prophylaxis is 960mg q2d administered on Monday, Wednesday and Friday; it should last until 10mg q 24h of prednisone is reached.
Relapse treatment In case of relapse suspicion the workup should be the same as initial starting from the diagnostic period. The treatment scheme is as in Arm A.
Follow-up period The observation starts from the first day of the maintenance therapy. The clinical and radiological follow-up is planned each 4-6 weeks during the first 24 weeks and then each 12 weeks. The observation will last up to 52 weeks. In the follow-up points steroid side effects, anticancer response, treatment efficacy and signs of relapse will be evaluated, using:
In the 12 weeks (t12) and 52 weeks (t52) point follow-up extra procedures to exaluate the endpoint will be performed:
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85 participants in 2 patient groups
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Data sourced from clinicaltrials.gov
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