Cyclosporine A in the TReatment of Interstitial Pneumonitis Associated With Sjogren's Syndrome (CTRIPS)

Cyclosporine A in the TReatment of Interstitial Pneumonitis Associated With Sjogren's Syndrome(CTRIPS): A Prospective, Randomized, Multicenter, Double-Blind Placebo-Controlled Trial

The purpose of this large multicenter, randomized, double-blinded, controlled clinical study is to investigate the efficacy and safety of Cyclosporin A for primary Sjogren's syndrome associated pneumonitis(pSS-IP), which has important implications for the establishment of standardized diagnosis and treatment of pSS-IP.

Study Overview

• Status: Unknown
• Conditions: Sjogren's Syndrome
• Intervention / Treatment: Drug: Cyclosporin A; Drug: Prednisone; Drug: Calcium carbonate D; Drug: Placebo

• Study Type: Interventional
• Enrollment (Anticipated): 240
• Phase: Phase 4

Contacts and Locations

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 110044
      • Recruiting
      • Peking University People's Hospital
      • Contact: Yue Yang, MD; Phone Number: +86-10-88325230; Email: yyang216@icloud.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients meeting the 2002 or 2012 pSS criteria;
• Patients meeting the diagnostic criteria of interstitial pneumonitis(IP);
• Patients with exertional dyspnea consistent with grade 2 on the Magnitude of Task component of the Mahler Modified Dyspnea Index;
• Pulmonary function test: patients with percentages of forced vital capacity (FVC) to predicted values≥45%, percentage of diffusing capacity of carbon monoxide (DLco) to predicted values≥30%, forced expiratory volume in one second (FEV1) / FVC> 65%;
• For patients who received oral glucocorticoid, the doses should be no more than 10 mg/d (or equivalent amount of other types of glucocorticoids);
• Patients who had not received any prior treatment with immunosuppressants (including but not limited to CYC, CsA, azathioprine(AZA), tacrolimus(FK-506), methotrexate, leflunomide, etc.) or had discontinued the therapy above for at least 3 months; for patients who received hydrochloroquine(HCQ), the doses should be stabilized for at least 3 months;
• Patients who had not received any prior treatment with biological agents, including but not limited to rituximab, infliximab, adalimumab, etanercept, etc., or had discontinued therapy for at least three months;
• For patients who had prior treatment with N-acetylcysteine, the doses of above drugs should be stabilized for at least 3 months;
• The women of reproductive age who had a negative urine pregnancy test. The women and men of reproductive age must receive effective contraceptive measures from the screening period to last administration of drugs;
• Patients who were able to read, to understand and to sign informed consent.

Exclusion Criteria: Patients who met any of the following criteria will not participate in this study.

• Patients with acute exacerbation of IP(AEIP);
• Arterial blood gas analysis showed respiratory failure;

• Patients with lung diseases other than IP:

  1. Patients with severe pulmonary hypertension who require specific treatments assessed by the rheumatology and immunology experts in various clinical centers;
  2. Patients with a history of smoking within the last 6 months or current smokers;
  3. Patients with other serious lung diseases, such as lung tumor or active pulmonary infection;
  4. Lung biopsy, alveolar lavage or high-resolution computerized tomography (HRCT) suggested serious lung diseases other than IP;
• Patients with other rheumatic autoimmune diseases, including but not limited to rheumatoid arthritis, systemic lupus erythematosus, inflammatory myopathy, systemic sclerosis, primary biliary cirrhosis, etc.;

• Patients with serious heart, liver, kidney diseases, hematologic and/ or endocrine diseases:

  1. Heart diseases: decompensated heart failure or refractory hypertension; clinically important abnormal ECG that may lead to unacceptable risks to enrolled patients at screening;
  2. Liver function: alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≥2 times the upper limit of normal (ULN);
  3. Renal function: renal tubular and/or interstitial diseases, renal insufficiency: serum creatinine≥2 ULN or glomerular filtration rate (eGFR) <90 ml/min/1.73 m2;
  4. White blood cell (WBC) count <3 ×109/L and/or hemoglobin (Hb) <100 g/L and/or platelet (PLT) count <80×109 /L;
  5. Other serious diseases: such as cancer, etc.;
• Patients with active infection or other diseases which will be aggravated with treatment of glucocorticoid and immunosuppressive therapy;
• Patients positive for HBsAg or hepatitis C antibody;
• Women during pregnancy or lactation, or cannot guarantee effective contraception;
• Patients who did not cooperate with treatment for mental illness or other reasons;
• Patients who had allergic constitution or were allergic to many drugs;
• Patients who were allergic or intolerant to CsA, CYC, or glucocorticoid.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cyclosporin A(CsA)+glucocorticoid; A. The efficacy/safety are evaluated at V3, V4, V5 and V6, and the treatment is adjusted accordingly. Patients who experienced treatment failure (FVC absolute decrease >15% of predicted values after 4 weeks of treatment) are suggested to switch to intravenous glucocorticoid + cyclophosphamide(CYC) 0.5-1 g/m2 every 4 weeks as the rescue therapy after unblinding, and continue to complete the subsequent follow-up. Each patient can only have one chance to be rescued. Patients who experience a second treatment failure should be withdrawn from the trial and be given empirical treatment. Patients who did not experience treatment failure continued to receive current treatment. B. For subjects with aggravated shortness of breath and dyspnea in between of two consecutive visits, the investigators should decide whether a visit should be increased to complete subsequent examinations.	Drug: Cyclosporin A; CsA 2-3 mg/kg/d, BID PO; Other Names: Cyclosporin A Capsules, CsA soft capsules 25 mg, Hangzhou China-US East China pharmaceutical Co., Ltd.; Drug: Prednisone; Prednisone 0.5mg/kg/d QD PO starting at Week 0. After 2-4 weeks, the initial dose is gradually tapered by 2.5 mg each week until a maintenance dosage of 5-7.5 mg/d through week 52 (visit 6). The initial and maintenance doses are determined by the investigators of each center depending on the patients.; Drug: Calcium carbonate D; Calcium carbonate D 600 mg, QD PO
Placebo Comparator: placebo+glucocorticoid; A. The efficacy/safety are evaluated at V3, V4, V5 and V6, and the treatment is adjusted accordingly. Patients who experienced treatment failure are suggested to switch to glucocorticoid + CsA 2-3mg/kg/d, BID as the rescue therapy, and continue to complete the subsequent follow-up. Each patient can only have one chance to be rescued. Patients who did not experience treatment failure continued to receive current treatment. B. For subjects with aggravated shortness of breath and dyspnea in between of two consecutive visits, the investigators in each center should decide whether a visit should be increased.	Drug: Prednisone; Prednisone 0.5mg/kg/d QD PO starting at Week 0. After 2-4 weeks, the initial dose is gradually tapered by 2.5 mg each week until a maintenance dosage of 5-7.5 mg/d through week 52 (visit 6). The initial and maintenance doses are determined by the investigators of each center depending on the patients.; Drug: Calcium carbonate D; Calcium carbonate D 600 mg, QD PO; Drug: Placebo; Placebo tablet 2-3 mg/kg/d, BID PO

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The forced vital capacity (FVC)	The FVC is expressed as percent of expected values corrected baseline level.	the 52 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
The diffusing capacity of carbon monoxide (DLco)	the 52 weeks

Collaborators and Investigators

• Sponsor: Peking University People's Hospital
• Investigators: Principal Investigator: Zhanguo Li, MD, Peking University People's Hospital

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2015
• Primary Completion (Anticipated): March 1, 2021
• Study Completion (Anticipated): December 1, 2021

Study Registration Dates

• First Submitted: February 18, 2015
• First Submitted That Met QC Criteria: February 18, 2015
• First Posted (Estimate): February 25, 2015

Study Record Updates

• Last Update Posted (Actual): May 22, 2020
• Last Update Submitted That Met QC Criteria: May 22, 2020
• Last Verified: May 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Immune System Diseases; Autoimmune Diseases; Lung Diseases; Eye Diseases; Disease; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Stomatognathic Diseases; Mouth Diseases; Lacrimal Apparatus Diseases; Arthritis, Rheumatoid; Xerostomia; Salivary Gland Diseases; Dry Eye Syndromes; Syndrome; Pneumonia; Lung Diseases, Interstitial; Sjogren's Syndrome; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Dermatologic Agents; Calcium-Regulating Hormones and Agents; Antifungal Agents; Calcineurin Inhibitors; Antacids; Calcium; Prednisone; Calcium Carbonate; Cyclosporine; Cyclosporins
• Other Study ID Numbers: 2014-M03; U1111-1167-1974 (Other Identifier: WHO ICTRP); ChiCTR-IPR-15005990 (Registry Identifier: Chinese Clinical Trial Registry)