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TB Host Directed Therapy (TBHDT)

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ClinicalTrials.gov Identifier: NCT02968927
Recruitment Status : Unknown
Verified January 2019 by The Aurum Institute NPC.
Recruitment status was:  Active, not recruiting
First Posted : November 21, 2016
Last Update Posted : January 10, 2019
Sponsor:
Information provided by (Responsible Party):
The Aurum Institute NPC

Tracking Information
First Submitted Date  ICMJE September 8, 2016
First Posted Date  ICMJE November 21, 2016
Last Update Posted Date January 10, 2019
Actual Study Start Date  ICMJE November 2016
Actual Primary Completion Date September 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 17, 2016)
SAEs and SUSARs [ Time Frame: through day 180 ]
For auranofin, everolimus, and vitamin D: the proportions of patients experiencing suspected unexpected serious adverse reactions (SUSARs). For CC-11050: the proportion of patients experiencing treatment emergent serious adverse events (SAEs).
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 17, 2016)
  • TEAEs other than SAEs and SUSARs [ Time Frame: through day 180 ]
    TEAEs other than SAEs, categorized according to severity, drug relatedness, and leading to early withdrawal.
  • Sputum culture status on day 56 [ Time Frame: day 56 ]
    Proportion of patients with positive sputum cultures on solid culture medium after 8 weeks of treatment
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: November 17, 2016)
  • Change in FEV1 from baseline to 2 and 6 months [ Time Frame: days 56 and 180 ]
    FEV1 (% of expected value)
  • 18F-FDG PET/CT imaging (change from baseline to 2 months): [ Time Frame: day 56 ]
    Maximum and mean standardized uptake values (SUV)
  • Serum neopterin [ Time Frame: day 56 ]
    change from baseline b. CRP
  • Quantiferon gold in tube [ Time Frame: day 56 ]
    change from baseline
  • Gene expression profiles (exploratory) [ Time Frame: days 56 and 180 ]
    Change from baseline to 2 and 6 months in gene expression profiles
  • PD-1 expression (exploratory) [ Time Frame: days 56 and 180 ]
    PD-1 expression on CD4 and CD8 lymphocytes
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE TB Host Directed Therapy
Official Title  ICMJE A Ph2 Randomized Trial to Evaluate the Safety Preliminary Efficacy and Biomarker Response of Host Directed Therapies Added to Rifabutin-modified Standard Therapy in Adults With Drug-Sensitive Smear-Positive Pulmonary TB
Brief Summary To examine the safety and preliminary efficacy of multiple adjunctive host directed TB therapies (TB HDT), to assess their potential to shorten TB treatment and/or prevent permanent lung damage.
Detailed Description

OBJECTIVES:

To determine the safety and preliminary efficacy of 4 TB HDT candidates:

  1. Safety (treatment emergent serious adverse events and SUSARs)
  2. Microbiologic effects in sputum (culture conversion, change in MGIT TTP) and blood (WBA)
  3. PET/CT imaging
  4. Serum markers of inflammation
  5. Effects on Mtb-specific and general immune function
  6. Pulmonary effects (spirometry, 6MWT, O2 saturation, and St. George Respiratory Symptom Questionnaire) In each case, TB HDT effects will be determined by comparison to patients treated with standard TB therapy alone with regard to a common set of primary and secondary endpoints.

PRIMARY ENDPOINTS

  1. For auranofin, everolimus, and vitamin D: the proportions of patients experiencing suspected unexpected serious adverse reactions (SUSARs).
  2. For CC-11050: the proportion of patients experiencing treatment emergent serious adverse events (SAEs).
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Tuberculosis
Intervention  ICMJE
  • Drug: Everolimus 0.5 MG
  • Drug: Auranofin 6 MG
  • Drug: Vitamin D3
  • Drug: CC-11050
  • Drug: 2HRbZE/4HRb
    Other Name: rifabutin-modified TB therapy
Study Arms  ICMJE
  • Active Comparator: 2HRbEZ/4HRb
    2HRbZE
    Intervention: Drug: 2HRbZE/4HRb
  • Experimental: Everolimus
    Everolimus 0.5 MG
    Interventions:
    • Drug: Everolimus 0.5 MG
    • Drug: 2HRbZE/4HRb
  • Experimental: Auranofin
    Auranofin 6 MG
    Interventions:
    • Drug: Auranofin 6 MG
    • Drug: 2HRbZE/4HRb
  • Experimental: Vitamin D
    Vitamin D3
    Interventions:
    • Drug: Vitamin D3
    • Drug: 2HRbZE/4HRb
  • Experimental: CC-11050
    CC-11050
    Interventions:
    • Drug: CC-11050
    • Drug: 2HRbZE/4HRb
Publications * Wallis RS, Ginindza S, Beattie T, Arjun N, Likoti M, Edward VA, Rassool M, Ahmed K, Fielding K, Ahidjo BA, Vangu MDT, Churchyard G. Adjunctive host-directed therapies for pulmonary tuberculosis: a prospective, open-label, phase 2, randomised controlled trial. Lancet Respir Med. 2021 Aug;9(8):897-908. doi: 10.1016/S2213-2600(20)30448-3. Epub 2021 Mar 16. Erratum in: Lancet Respir Med. 2021 Jun;9(6):e55.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Unknown status
Actual Enrollment  ICMJE
 (submitted: November 17, 2016)
200
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2020
Actual Primary Completion Date September 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Willing and able to provide signed written consent or witnessed oral consent in the case of illiteracy, prior to undertaking any trial-related procedures.
  2. Aged 18 to 65 years, male, or if female, either not of reproductive potential (post-menopause, or status-post surgical sterilization) or with an intrauterine contraceptive device in place.
  3. Body weight (in light clothing without shoes) between 40 and 90 kg.
  4. First episode of pulmonary tuberculosis diagnosed by positive sputum AFB smear with subsequent culture confirmation OR positive Xpert TB/RIF with Ct <20 [4].
  5. RIF susceptibility diagnosed by Xpert TB/RIF OR Hain test
  6. Chest radiograph meeting criteria for moderate or far advanced pulmonary tuberculosis [5]
  7. HIV-1 seronegative
  8. HBsAg negative

Exclusion Criteria:

  1. Any condition for which participation in the trial, as judged by the investigator, could compromise the well-being of the subject or prevent, limit or confound protocol specified assessments
  2. Current or imminent treatment for malaria.
  3. Is critically ill, and in the judgment of the investigator has a diagnosis likely to result in death during the trial or the follow-up period.
  4. TB meningitis or other forms of severe tuberculosis with high risk of a poor outcome as judged by the investigator.
  5. History of allergy or hypersensitivity to any of the trial therapies or related substances, including known allergy or suspected hypersensitivity to rifampin or rifabutin.
  6. Having participated in other clinical trials with investigational agents within 8 weeks prior to trial start or currently enrolled in an investigational trial.
  7. Subjects with any of the following at screening:

    1. Cardiac arrhythmia requiring medication;
    2. Prolongation of QT/QTc interval with QTcF (Fridericia correction) >450 ms;
    3. History of additional risk factors for Torsade de Pointes, (e.g., heart failure, hypokalemia, family history of Long QT Syndrome);
    4. Any clinically significant ECG abnormality, in the opinion of the investigator.
    5. Patients requiring concomitant medications that prolong the QT inter-val.
  8. Random blood glucose >140 mg/dL, or history of unstable Diabetes Mellitus which required hospitalization for hyper- or hypoglycaemia within the past year prior to start of screening.
  9. Use of systemic corticosteroids within the past 28 days.
  10. Subjects with any of the following abnormal laboratory values:

    1. creatinine >2 mg/dL
    2. haemoglobin <8 g/dL
    3. platelets <100x109 cells/L
    4. serum potassium <3.5
    5. aspartate aminotransferase (AST) ≥2.0 x ULN
    6. alkaline phosphatase (AP) >5.0 x ULN
    7. total bilirubin >1.5 mg/dL
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE South Africa
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02968927
Other Study ID Numbers  ICMJE TBHDT-AUR1-8-178
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party The Aurum Institute NPC
Study Sponsor  ICMJE The Aurum Institute NPC
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Robert S Wallis, MD,FIDSA The Aurum Institute NPC
PRS Account The Aurum Institute NPC
Verification Date January 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP