Safety and Efficacy of Blocking IL-4 With Pascolizumab in Patients Receiving Standard Combination Therapy for Pulmonary Tuberculosis (TB)

This study is currently recruiting participants. (see Contacts and Locations)
Verified October 2014 by National University Hospital, Singapore
Sponsor:
Collaborator:
National University, Singapore
Information provided by (Responsible Party):
National University Hospital, Singapore
ClinicalTrials.gov Identifier:
NCT01638520
First received: July 9, 2012
Last updated: October 14, 2014
Last verified: October 2014
  Purpose

New approaches are needed to achieve more rapid elimination of dormant mycobacteria and thereby shorten treatment for drug-sensitive and drug-resistant tuberculosis (TB). Dormant mycobacteria are relatively resistant to antibacterial drugs and approaches that enhance immune clearance have the potential to be more effective. Interleukin-4 (IL-4) is a key cytokine in the immune response to TB that may impair the clearance of mycobacteria. We hypothesize that pascolizumab, an anti-IL-4 monoclonal antibody, might be of value as an adjunct to standard treatment.

The aims of this trial are to determine whether administration of pascolizumab as an adjunct to standard combination treatment for drug-sensitive TB produces changes in one or more parameters of bacterial or host response (including bacterial clearance, host clinical status, immune response, bacterial and host transcriptomics, lung imaging) that may indicate potential for enhanced sterilization and to confirm the safety of blocking IL-4 (previously demonstrated in healthy volunteers and patients with asthma) in patients with TB.


Condition Intervention Phase
Tuberculosis, Pulmonary
Drug: Pascolizumab
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: Safety and Efficacy of Blocking IL-4 With Pascolizumab in Patients Receiving Standard Combination Therapy for Pulmonary Tuberculosis (TB): a Randomized, Double-blind, Placebo-controlled, Proof-of-concept Clinical Trial

Resource links provided by NLM:


Further study details as provided by National University Hospital, Singapore:

Primary Outcome Measures:
  • Efficacy - Time to detection on liquid culture of sputum on Week 8 [ Time Frame: 8 weeks post intervention ] [ Designated as safety issue: No ]
  • Co-primary outcome measure - safety [ Time Frame: Upto 24 weeks via follow-up visits/assessments and 24-96 weeks via phone assessments ] [ Designated as safety issue: Yes ]
    Adverse events considered at least possibly related to study medication and that are classified by the site investigator as serious and/or grade IV severity


Secondary Outcome Measures:
  • Sputum culture status (positive or negative) on liquid culture at week 8 [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
  • Rate of change (area under the curve) from baseline to week 8 in the time to positivity in liquid culture of sputum [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
  • Rate of change in serial sputum colony counts on solid cultures from baseline to week 8 [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
  • Rate of change of RPF-dependent serial sputum colony counts from baseline to week 8 [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
  • Sputum culture status (positive or negative) on solid culture at week 8 [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
  • Rate of change of sputum smear lipid-body positive mycobacteria from baseline to week 8 [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
  • Serum IL-4 levels (free and drug-bound) [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
  • Time to resolution of fever [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
  • Time to resolution of all TB symptoms [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
  • Resolution of chest X-ray changes at week 24 [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
  • Resolution of PET/MRI changes at week 8 and week 24 [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
  • TB relapse at any time up to week 96 [ Time Frame: 96 weeks ] [ Designated as safety issue: No ]
  • Anti-pascolizumab antibodies [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]

Estimated Enrollment: 56
Study Start Date: June 2012
Estimated Study Completion Date: June 2016
Estimated Primary Completion Date: October 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Saline Drug: Placebo
5ml of Saline
Experimental: Pascolizumab Drug: Pascolizumab
0.05mg/kg - 10mg/kg Pascolizumab according to dosing cohort

  Eligibility

Ages Eligible for Study:   21 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Aged 21 -75 years of age
  2. Male or female: females eligible only if not of childbearing potential or agree to remain abstinent or use an appropriate contraceptive method during the study.
  3. Confirmed pulmonary TB by smear microscopy and Gene Xpert™
  4. Absence of rifampicin resistance on molecular probe (Gene Xpert™)
  5. Estimated to be able to produce at least 5ml of sputum per 24 hour period.
  6. No previous history of anti-TB therapy for active disease (treatment for latent disease acceptable).
  7. Willing to comply with the study visits and procedures
  8. Willing and able to provide written informed consent

Exclusion Criteria:

  1. More than 28 days of standard anti-TB chemotherapy at the time of randomization.
  2. Disseminated TB (lymphadenopathy is acceptable)
  3. Underlying serious chronic diseases such as those of the liver, kidney disease, blood disorders and Type I diabetes (controlled Type II diabetes is acceptable) or any significant organ dysfunction.
  4. History of myocardial infarction, congestive heart failure or arrhythmia within 6 months of screening
  5. History or evidence of chronic alcohol consumption or drug abuse
  6. Current autoimmune disease or history of autoimmune disease.
  7. Known or suspected hypersensitivity to any component of the trial medication (sodium phosphate, sodium chloride, glycine, sucrose, polysorbate 80)
  8. Chronic use of an immunosuppressant
  9. Treatment with any monoclonal antibody within 6 months of randomization
  10. Vaccination within the 6 weeks prior to randomization (patients who have received influenza vaccination can enroll at 2 weeks following vaccination).
  11. Seropositive for human immunodeficiency virus-1 or 2; hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) antibodies at screening
  12. Creatinine > 1.4 times upper limit of normal or ALT greater than 2.5 times upper limit of normal on screening blood tests
  13. QTc >450 msec on ECG performed at screening
  14. Women who are currently pregnant or breastfeeding
  15. Any other significant condition that would, in the opinion of the investigator, compromise the patient's safety or outcome in the trial.
  16. Participation in other clinical intervention trial or research protocol (Participation in other studies that do not involve an intervention may be allowed, but this must be discussed and approved by Chief Investigator )
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01638520

Contacts
Contact: Meera Gurumurthy +65 90018835 mdcgm@nus.edu.sg

Locations
Singapore
National University Hospital, Singapore Recruiting
Singapore, Singapore
Contact: Meera Gurumurthy    +65 90018835    mdcgm@nus.edu.sg   
Sponsors and Collaborators
National University Hospital, Singapore
National University, Singapore
Investigators
Principal Investigator: Nick Paton National Univesity, Singapore
  More Information

No publications provided

Responsible Party: National University Hospital, Singapore
ClinicalTrials.gov Identifier: NCT01638520     History of Changes
Other Study ID Numbers: DSRB 2012/02212
Study First Received: July 9, 2012
Last Updated: October 14, 2014
Health Authority: Singapore: Domain Specific Review Boards
Singapore: Health Sciences Authority

Keywords provided by National University Hospital, Singapore:
Immune Therapy
Interleukin 4
monoclonal antibody

Additional relevant MeSH terms:
Tuberculosis
Tuberculosis, Pulmonary
Actinomycetales Infections
Bacterial Infections
Gram-Positive Bacterial Infections
Lung Diseases
Mycobacterium Infections
Respiratory Tract Diseases
Respiratory Tract Infections

ClinicalTrials.gov processed this record on October 21, 2014