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

NCT01638520 | Unknown Phase 2 DMC

• 1 other identifier: DSRB 2012/02212
• Study Type: interventional
• Target: 32
• Locations: 3 countries
• Sites: 7

Brief Summary

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.

Conditions

Tuberculosis, Pulmonary

Keywords

Immune Therapy; Interleukin 4; monoclonal antibody

Outcome Measures

Primary Outcomes (2)

• Efficacy - Time to detection on liquid culture of sputum on Week 8

  8 weeks post intervention

• Co-primary outcome measure - safety

  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

  Upto 24 weeks via follow-up visits/assessments and 24-96 weeks via phone assessments

Secondary Outcomes (13)

• Sputum culture status (positive or negative) on liquid culture at week 8

  8 weeks

• Rate of change (area under the curve) from baseline to week 8 in the time to positivity in liquid culture of sputum

  8 weeks

• Rate of change in serial sputum colony counts on solid cultures from baseline to week 8

  8 weeks

• Rate of change of RPF-dependent serial sputum colony counts from baseline to week 8

  8 weeks

• Sputum culture status (positive or negative) on solid culture at week 8

  8 weeks

Study Arms (2)

Pascolizumab

EXPERIMENTAL

The dose of study medication will be calculated using the patient's body weight and the appropriate dosing regimen based on the cohort of enrollment. The medication will be administered by slow intravenous infusion over 1 hour under close medical supervision.

Drug: Pascolizumab

Placebo

PLACEBO COMPARATOR

For patients randomized to placebo, Sterile 0.9% w/v Sodium Chloride will be used for Injection, using the same volume that would have been prepared if the patient had been randomized to receive pascolizumab.

Drug: Placebo

Interventions

Pascolizumab DRUG

0.05mg/kg - 10mg/kg Pascolizumab according to dosing cohort

Pascolizumab

Placebo DRUG

Saline (volume determined based on weight of patient, and cohort of enrollment)

Placebo

Eligibility Criteria

• Age: 21 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Aged 21 -75 years of age
• 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.
• Confirmed pulmonary TB by smear microscopy and Gene Xpert™
• Absence of rifampicin resistance on molecular probe (Gene Xpert™)
• Estimated to be able to produce at least 5ml of sputum per 24 hour period.
• No previous history of anti-TB therapy for active disease (treatment for latent disease acceptable).
• Willing to comply with the study visits and procedures
• Willing and able to provide written informed consent

You may not qualify if:

• More than 28 days of standard anti-TB chemotherapy at the time of randomization.
• Disseminated TB (lymphadenopathy is acceptable)
• 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.
• History of myocardial infarction, congestive heart failure or arrhythmia within 6 months of screening
• History or evidence of chronic alcohol consumption or drug abuse
• Current autoimmune disease or history of autoimmune disease.
• Known or suspected hypersensitivity to any component of the trial medication (sodium phosphate, sodium chloride, glycine, sucrose, polysorbate 80)
• Chronic use of an immunosuppressant
• Treatment with any monoclonal antibody within 6 months of randomization
• Vaccination within the 6 weeks prior to randomization (patients who have received influenza vaccination can enroll at 2 weeks following vaccination).
• Seropositive for human immunodeficiency virus-1 or 2; hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) antibodies at screening
• Creatinine \> 1.4 times upper limit of normal or ALT greater than 2.5 times upper limit of normal on screening blood tests
• QTc \>450 msec on ECG performed at screening
• Women who are currently pregnant or breastfeeding
• Any other significant condition that would, in the opinion of the investigator, compromise the patient's safety or outcome in the trial.

Sponsors & Collaborators

• National University Hospital, Singapore: lead
• National University of Singapore: collaborator

Study Sites (7)

Institute of Respiratory Medicine

Kuala Lumpur, Malaysia

Location

University Malaya Medical Centre

Kuala Lumpur, Malaysia

Location

Lung Centre Philippines

Manila, Philippines

Location

Philippines Tuberculosis Society Inc.

Manila, Philippines

Location

Changi General Hospital

Singapore, Singapore

Location

National University Hospital, Singapore

Singapore, Singapore

Location

Ng Teng Fong General Hospital

Singapore, Singapore

Location

Related Publications (1)

• Paton NI, Gurumurthy M, Lu Q, Leek F, Kwan P, Koh HWL, Molton J, Mortera L, Naval S, Bakar ZA, Pang YK, Lum L, Lim TK, Cross GB, Lekurwale G, Choi H, Au V, Connolly J, Hibberd M, Green JA; Pascolizumab Tuberculosis Trial Team. Adjunctive Pascolizumab in Rifampicin-Susceptible Pulmonary Tuberculosis: Proof-of-Concept, Partially-Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Trial. J Infect Dis. 2024 Sep 23;230(3):590-597. doi: 10.1093/infdis/jiae104.

  PMID: 38527849 DERIVED

MeSH Terms

Conditions

Tuberculosis, Pulmonary

Condition Hierarchy (Ancestors)

Tuberculosis; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases

Study Officials

• Nick Paton

  National Univesity, Singapore

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 9, 2012
• First Posted: July 11, 2012
• Study Start: June 1, 2012
• Primary Completion: February 1, 2017
• Study Completion: July 1, 2017
• Last Updated: April 4, 2017

Record last verified: 2017-03

Locations

SG (3); PH (2); MY (2)