LOTUSS

Inclusion Criteria

Demographic Characteristics:

  1. Male and female patients, aged 18-70 years (inclusive) on Day 1

SSc- and SSc-ILD-Related Criteria:

  1. Diagnosis of SSc confirmed by the investigator using the preliminary criteria of the American College of Rheumatology for the classification of systemic sclerosis
  2. Duration of diagnosis <7 years (dated from the onset of the first non‑Raynaud’s phenomenon manifestation, to Day 1 of the study)
  3. Diagnosis of SSc-ILD based on an HRCT scan (obtained in the 2 years before the date of written informed consent) that demonstrates findings consistent with ILD, as assessed by the investigator
  4. Screening FVC ≥50% of the predicted value, and screening DLCO ≥40% of the predicted value
  5. At study entry, the patient either is not taking SSc-ILD medication or is taking cyclophosphamide or MMF, as described below:
  6. Not on SSc-ILD medication: Has not taken SSc-ILD medication in the 3 months before Day 1, or will complete appropriate washout of SSc-ILD medication by Day 1; for such patients, there must be no plan to start another SSc-ILD medication during the study
  7. Taking cyclophosphamide or MMF: Is on an oral formulation of cyclophosphamide (≤2 mg/kg/d) or MMF (≤1.5 g two times daily [BID]), and the dose has been stable in the 3 months before Day 1; for such patients, there must be no plan to change that SSc-ILD medication or its dose during the study

Informed Consent and Protocol Adherence:

  1. Able to understand and sign a written informed consent form
  2. Able to understand the importance of adhering to study treatment and the study protocol, and willing to follow all study requirements, including the concomitant medication restrictions, throughout the study
  3. Use of effective contraception: Women of childbearing potential are required to have a negative pregnancy test before treatment and must agree to maintain highly effective contraception by practicing abstinence or by using at least two methods of birth control from the date of consent through the end of the study. If abstinence is not practiced, one of the two methods of birth control must be an oral contraceptive (e.g., oral contraceptive and spermicide).

Exclusion Criteria

Disease-Related Exclusions:

  1. Clinically significant pulmonary hypertension, based on any of the following criteria (Galiè et al. 2009 and McLaughlin et al. 2009):
  2. Receiving treatment for pulmonary hypertension
  3. Or, if available, a previous right heart catheterization that demonstrates mean pulmonary artery pressure at rest of ≥25 mm Hg with concurrent wedge pressure of ≤15 mm Hg and pulmonary vascular resistance of >3 Wood units
  4. Or, Doppler echocardiography in the 6 months before Day 1 with an estimated systolic pulmonary arterial pressure (Ppa) of >36 mm Hg corresponding to a tricuspid regurgitant jet velocity of >2.8 m/sec
  5. Evidence of right atrial or ventricular enlargement or significant left ventricular dysfunction
  6. Known underlying liver disease (e.g., hepatitis or cirrhosis)
  7. Clinical evidence of significant aspiration or uncontrolled gastroesophageal reflux (i.e., University of California, Los Angeles, Scleroderma Clinical Trial Consortium Gastrointestinal Scale, 2.0 [UCLA SCTC GIT 2.0] reflux score >1.00), as assessed by the investigator
  8. Known achalasia, esophageal stricture, or esophageal dysfunction sufficient to limit the ability to swallow oral medication
  9. Tobacco smoking within 3 months of screening or unwillingness to avoid smoking throughout the study (e.g., cigarette, pipe, cigar)
  10. History of a clinically significant environmental exposure that is known to cause pulmonary fibrosis (PF) including, but not limited to, drugs (e.g., amiodarone), asbestos, beryllium, radiation, or domestic birds or other factors associated with hypersensitivity pneumonitis
  11. History of clinically significant asthma as an adult or clinically significant chronic obstructive pulmonary disease, as assessed by the investigator

Medical Exclusions:

  1. Clinical evidence of active infection including, but not limited to, bronchitis, pneumonia, sinusitis, or urinary tract infection.

10.  Features supporting diagnosis of another connective-tissue disorder (e.g., rheumatoid arthritis or systemic lupus erythematous) or another pulmonary disorder (e.g., emphysema, asthma, cancer)

11.  Expected to have study participation interrupted for a foreseeable medical or surgical event (e.g., organ, stem cell, or bone marrow transplant).

12.  Any clinical evidence of a malignancy that is likely to result in significant disability or likely to require significant medical or surgical intervention within the next 6 months (relative to Day 1). This does not include minor surgical procedures for localized cancer (e.g., basal cell carcinoma).

13.  Any condition (other than SSc-ILD) that is likely to result in the death of the patient within 12 months, as assessed by the investigator

14.  History of unstable or deteriorating cardiac or pulmonary disease (other than SSc‑ILD) within the previous 6 months (relative to Day 1) including, but not limited to, the following:

  1. Unstable angina pectoris
  2. Myocardial infarction
  3. Congestive heart failure requiring hospitalization
  4. Uncontrolled clinically significant arrhythmia
  5. Pulmonary hypertension (as described in Exclusion Criterion 1)

15.  Any condition that, as assessed by the investigator, might be significantly exacerbated by the known side effects associated with pirfenidone

16.  Known or suspected peptic ulcer

17.  Pregnancy or lactation: Positive pregnancy test; currently lactating; or for women of childbearing potential, an unwillingness to maintain highly effective contraception, as described in Inclusion Criterion 8

18.  History of alcohol or substance abuse in the previous 2 years (relative to Day 1)

19.  Family or personal history of long QT syndrome

Laboratory Exclusions:

20.  Any of the following liver test criteria above the specified limit:

  1. Total bilirubin above the ULN, except in patients with predominantly unconjugated hyperbilirubinemia (e.g., Gilbert’s syndrome)
  2. Aspartate or alanine aminotransferase (AST or ALT) >2 ´ ULN
  3. Alkaline phosphatase >2 ´ ULN
  4. Creatinine clearance <40 mL/min, calculated using the Cockcroft-Gault formula

Medication Exclusions:

21.  Any prior use of pirfenidone

22.  Suspected intolerance, allergy, or hypersensitivity to pirfenidone or any of its excipients

23.  Use of any investigational drug in the 28 days before screening (an investigational drug is defined as any drug that has not been approved for marketing for any indication in the country of the participating site)

24.  Ongoing use or expected use of any of the following therapies:

  1. Investigational therapy (an investigational drug is defined as any drug that has not been approved for marketing for any indication in the country of the participating site)
  2. Strong inhibitors of CYP1A2 (e.g., fluvoxamine or enoxacin)
  3. Moderate inhibitors of CYP1A2 (e.g., mexiletine, thiabendazole, or phenylpropanolamine [Note: ciprofloxacin will be allowed only at doses ≤500 mg BID])
  4. Moderate inducers of CYP1A2 (e.g., tobacco smoking, montelukast, or phenytoin)
  5. Methotrexate
  6. Cyclosporine
  7. Azathioprine
  8. Rapamycin
  9. Oral corticosteroids at a dose >10 mg/d prednisone equivalent
  10. d-penicillamine
  11. Minocycline
  12. r-relaxin
  13. Interferon-g
  14. Endothelin-1 receptor antagonists (e.g., bosentan or ambrisentan)
  15. Phosphodiesterase inhibitors for the treatment of SSc-ILD (e.g., sildenafil or tadalafil); these drugs will be allowed if used for other indications (e.g., erectile dysfunction) or Raynaud’s phenomenon
  16. Tumor necrosis factor-α (TNF-α) neutralizing drugs or other biologics used to treat connective-tissue disorders
  17. Treatment with any UV spectrum-containing light, including lasers, and recreational use of any UV spectrum-containing light (e.g., tanning bed)

-       Exception: Therapeutic use of non-UV lasers will be allowed (e.g., lasers in the infrared spectrum)

General Exclusion:

25.  Unsuitable for enrollment or unlikely to comply with study requirements, as assessed by the investigator