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Study of Pharmacodynamics, Pharmacokinetics, Safety and Tolerability of VAY736 in Patients With Idiopathic Pulmonary Fibrosis

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ClinicalTrials.gov Identifier: NCT03287414
Recruitment Status : Recruiting
First Posted : September 19, 2017
Last Update Posted : December 7, 2018
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:
This study will investigate the safety and efficacy of VAY736 administered subcutaneously (s.c.) every 4 weeks for 48 weeks. Approximately, 84 subjects will be randomized in a 1:1 ratio on top of local standard of care (SOC), to receive VAY736 or placebo.

Condition or disease Intervention/treatment Phase
Idiopathic Pulmonary Fibrosis Drug: VAY736 Drug: Placebo Phase 2

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 84 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: A subject-, investigator-, and sponsor-blinded
Primary Purpose: Treatment
Official Title: A Subject-, Investigator-, and Sponsor-blinded, Randomized, Placebo-controlled, Multicenter Study to Investigate Efficacy, Safety, and Tolerability of VAY736 in Patients With Idiopathic Pulmonary Fibrosis
Actual Study Start Date : September 3, 2017
Estimated Primary Completion Date : April 6, 2022
Estimated Study Completion Date : April 6, 2022


Arm Intervention/treatment
Experimental: VAY736
VAY736 administered subcutaneously (s.c.) every 4 weeks
Drug: VAY736
VAY736 administered subcutaneously (s.c.) every 4 weeks

Placebo Comparator: Placebo
Placebo administered subcutaneously (s.c.) every 4 weeks
Drug: Placebo
Placebo administered s.c. every 4 weeks




Primary Outcome Measures :
  1. Change from baseline to end of treatment epoch (48 weeks of treatment) in Forced Vital Capacity (FVC). [ Time Frame: Baseline, Week 48 ]
    To assess the efficacy of VAY736 in patients with idiopathic pulmonary fibrosis Change from baseline to end of treatment epoch (48 weeks of treatment) in Forced Vital Capacity (FVC).


Secondary Outcome Measures :
  1. All-Cause mortality [ Time Frame: Week 48 ]
    To assess the impact of VAY736 on survival: All-cause mortality

  2. Progression-free survival (PFS) [ Time Frame: Week 48 ]

    Progression free survival analysis as defined will be produced at the end of the treatment epoch (week 48) for the following event of interest:

    1. Events, defined as: death (all-cause mortality) OR "progression" (relative reduction in FVC ≥ 10%)
    2. Events, defined as: death (IPF-related mortality) OR "progression" (relative reduction in FVC ≥ 10%)

  3. Disease progression [ Time Frame: Week 48 ]
    Disease Progression, defined as: a)relative reduction in FVC ≥ 10% b) relative reduction in Diffusing Capacity of the Lungs (DLCO) ≥ 15% c) absolute reduction in Six Minute Walk Distance (6MWD) ≥ 50 m

  4. Composite Endpoint [ Time Frame: Week 48 ]

    Composite Endpoint defined as:

    1. death (all-cause mortality), OR relative reduction in FVC≥10%, OR relative reduction in DLCO ≥15%, OR relative reduction in 6MWD ≥50m
    2. death (IPF-related morality), OR relative reduction in FVC≥10%, OR relative reduction in DLCO ≥15%, OR relative reduction in 6MWD ≥50m

  5. Change from baseline to end of treatment epoch (Week 48) in Diffusing Capacity of the Lungs (DLCO) [ Time Frame: Baseline, Week 48 ]
    To assess the impact of VAY736 on Pulmonary Physiology: Change from baseline to theend of treatment epoch (week 48) in DLCO

  6. Change from baseline to the end of treatment epoch (Week 48) in 6-minute walk test and in distance-saturation product [ Time Frame: Baseline, Week 48 ]
    Change from baseline to the end of treatment epoch (Week 48) in 6-minute walk test and in distance-saturation product to assess the impact of VAY736 on exercise capacity

  7. Change from baseline to the end of treatment epoch (Week 48) in resting oxygen saturation (on room air) [ Time Frame: Baseline, Week 48 ]
    Change from baseline to the end of treatment epoch (Week 48) in resting oxygen saturation (on room air) to assess the impact of VAY736 on gas exchange

  8. Immunogenicity of VAY736 [ Time Frame: Week 48 ]
    To assess the immunogenicity of VAY736 by measuring Serum anti-VAY736 antibodies

  9. To assess the pharmacokinetics Cmin,ss of VAY736 after multiple s.c. doses [ Time Frame: Day 1 through Week 69 ]
    Determine the Cmin,ss from the serum concentration (VAY736)-time data

  10. Idiopathic Pulmonary Fibrosis (IPF) -related Mortality [ Time Frame: Week 48 ]
    To assess the impact of VAY736 on survival: IPF-related mortality

  11. Change from baseline to end of treatment epoch (Week 48) in Total Lung Capacity (TLC) [ Time Frame: Baseline, Week 48 ]
    To assess the impact of VAY736 on Pulmonary Physiology: Change from baseline to the end of treatment epoch (week 48 ) in Total Lung Capacity (TLC).



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Ages Eligible for Study:   40 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Written informed consent must be obtained before any assessment is performed.
  2. Male and female subjects 40 to 80 years of age inclusive
  3. A diagnosis of definite or probable IPF within 5 years of the screening visit, as defined by Figure 3, Tables 4-6 of the ATS/ERS/JRS/ALAT Diagnostic Guidelines (Raghu et al 2011)
  4. Seropositive at screening for at least one of the following auto-antibodies: RF, ANA, anti-dsDNA, anti-CCP, Scl-70, SSA (anti-Ro), SSB (anti-La), anti-RNP, anti-Smith, Jo-1, PL-7, PL-12, EJ, OJ, SRP, Ku, Mi-2, anti-PM/Scl; OR Presence of hilar/mediastinal adenopathy (>1cm in short-axis diameter), identified by screening HRCT scan of the chest
  5. FVC 50-90% predicted (inclusive)
  6. DLCO, corrected for hemoglobin, 30-79% predicted (inclusive)
  7. FEV1/FVC >70%
  8. Unlikely to die from cause other than IPF within the next 3 years, in the opinion of the investigator
  9. Unlikely to undergo lung transplantation during this trial
  10. Able to communicate well with the investigator, to understand and comply with the requirements of the study.

Exclusion Criteria:

  1. Emphysema > fibrosis on screening HRCT (must be confirmed by central reader)
  2. Active viral, bacterial or other infections requiring systemic treatment at the time of screening or enrollment, or history of recurrent clinically significant infection or of bacterial infections with encapsulated organisms
  3. History of major organ, hematopoietic stem cell or bone marrow transplant
  4. History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes (e.g., mAb of IgG1 class) or to any of the constituents of the study drug (sucrose, L-Arginine hydrochloride, L-histidine, polysorbate 80, hydrochloric acid)
  5. Receipt of live/attenuated vaccine within a 2 month period before first dose
  6. History of primary or secondary immunodeficiency, including a positive Human Immunodeficiency Virus (HIV) (Enzyme-linked Immunosorbent Assay (ELISA) and Western blot) test result
  7. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin, in situ cervical cancer), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases
  8. Any one of the following screening values of complete blood count laboratory values: Hemoglobin levels below 8.0 g/dL; Total leukocyte count less than 2,000/μL; Platelets <100.0 x 109/L; Absolute neutrophil count (ANC) <1.5 x 109/L
  9. Any surgical, medical (e.g., uncontrolled hypertension, heart failure or diabetes), psychiatric or additional physical condition that the Investigator feels may jeopardize the patient in case of participation in this study
  10. Positive hepatitis B surface antigen (HBsAg) with concurrent negative hepatitis B surface antibody (anti-HBs); or positive total hepatitis B core antibody (anti-HBc) with concurrent negative anti-HBs; or positive hepatitis C antibody (anti-HCV) unless it can be documented that the patient has received highly-effective HCV-specific antiviral therapy, HCV RNA levels are measured, and HCV RNA is undetectable; i.e., any acute or chronic infection with hepatitis B or hepatitis C
  11. Evidence of active or latent tuberculosis (TB) infection, as determined by Quantiferon test (after anti-TB treatment, patients with history of or latent TB may become eligible according to national guidelines)
  12. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test
  13. Clinically diagnosed AE-IPF or other significant clinical worsening within 3 months of randomization
  14. Other known causes of interstitial lung disease (e.g., domestic or occupational environmental exposures, drug toxicity) or other identifiable interstitial lung disease
  15. Definitive diagnosis of a connective tissue disease (such as systemic sclerosis, DM/PM, RA, Sjogren's syndrome, or SLE)
  16. Initiation of pulmonary rehabilitation within 60 days of randomization (pulmonary rehabilitation is prohibited during the period of this trial, except for "maintenance" rehabilitation, to be documented with a clinical summary from the Rehabilitation Center)
  17. Myocardial Infarction (MI), Cerebrovascular Accident (CVA), Transient Ischemic Attack (TIA), or hospitalization for arrhythmia or unstable angina within 6 months
  18. New York Heart Association (NYHA) class III/IV Congestive Heart Failure (CHF), Ejection Fraction (EF) <25%
  19. Other investigational treatments within 6 months of screening
  20. Disability (other than dyspnea) that may limit the completion of 6MWT (angina, claudication, etc.)
  21. Current smoker (must have negative cotinine test)
  22. Any current treatment for IPF (except for pirfenidone or nintedanib; but not both)
  23. Historical (within 6 months of screening) treatment for IPF with experimental or off-label modalities including but not limited to oral corticosteroids, N-Acetylcysteine , cyclophosphamide, mycophenolate, azathioprine, cyclosporine A, etanercept, or plasmapheresis.
  24. Prior use of any B-cell depleting therapy (e.g., rituximab, ofatumumab, or other anti-CD20 mAb, anti-CD40, anti-CD19,anti-CD22 mAb, anti-CD52 mAb, or anti-BAFF mAb)
  25. Receiving any treatment for pulmonary hypertension OR treatment for pulmonary hypertension anticipated during this trial (in other words, treatment for pulmonary hypertension is prohibited during this trial), including but not limited to epoprostanil, iloprostanil, treprostanil, selexipag, bosentan, ambrisentan, macitentan, sildenafil, tadalafil, and riociguat.
  26. History of alcohol and/or drug abuse within the last 2 years
  27. Elective surgery planned to take place during this trial
  28. Women of child-bearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception for 3 months prior to screening, during dosing, and for 4 months after stopping of investigational medication.

Highly effective contraception methods include:

  • Total abstinence from heterosexual intercourse (when this is in line with the preferred and usual lifestyle of the patient). Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
  • Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking investigational drug. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.
  • Male sterilization (at least 6 months prior to screening). For female subjects on the study the vasectomized male partner should be the sole partner for that subject.
  • Use of oral (estrogen and progesterone), injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception. In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking investigational drug.

Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.


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): NCT03287414


Contacts
Contact: Novartis Pharmaceuticals 1-888-669-6682 Novartis.email@novartis.com
Contact: Novartis Pharmaceuticals +41613241111

Locations
United States, Alabama
Novartis Investigative Site Recruiting
Birmingham, Alabama, United States, 35294-0007
United States, Florida
Novartis Investigative Site Recruiting
Miami, Florida, United States, 33136
United States, Maryland
Novartis Investigative Site Recruiting
Baltimore, Maryland, United States, 21224
United States, New Hampshire
Novartis Investigative Site Recruiting
Lebanon, New Hampshire, United States, 03756
Canada
Novartis Investigative Site Recruiting
Quebec, Canada, GIV 4G5
Ireland
Novartis Investigative Site Recruiting
Dublin, Ireland, DUBLIN 4
Italy
Novartis Investigative Site Recruiting
Modena, Italy, 41124
Sponsors and Collaborators
Novartis Pharmaceuticals

Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT03287414     History of Changes
Other Study ID Numbers: CVAY736X2207
First Posted: September 19, 2017    Key Record Dates
Last Update Posted: December 7, 2018
Last Verified: December 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description:

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com


Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Fibrosis
Pulmonary Fibrosis
Idiopathic Pulmonary Fibrosis
Idiopathic Interstitial Pneumonias
Pathologic Processes
Lung Diseases
Respiratory Tract Diseases
Lung Diseases, Interstitial