TB Host Directed Therapy (TBHDT)

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

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.

Study Overview

• Status: Unknown
• Conditions: Tuberculosis
• Intervention / Treatment: Drug: 2HRbZE/4HRb; Drug: Everolimus 0.5 MG; Drug: Auranofin 6 MG; Drug: Vitamin D3; Drug: CC-11050

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: Interventional
• Enrollment (Actual): 200
• Phase: Phase 2

Contacts and Locations

Study Locations

• South Africa
  • Gauteng
    • Tembisa, Gauteng, South Africa, 1736
      • The Aurum Institute: Tembisa Clinical Research Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 2HRbEZ/4HRb; 2HRbZE	Drug: 2HRbZE/4HRb; Other Names: rifabutin-modified TB therapy
Experimental: Everolimus; Everolimus 0.5 MG	Drug: 2HRbZE/4HRb; Other Names: rifabutin-modified TB therapy; Drug: Everolimus 0.5 MG
Experimental: Auranofin; Auranofin 6 MG	Drug: 2HRbZE/4HRb; Other Names: rifabutin-modified TB therapy; Drug: Auranofin 6 MG
Experimental: Vitamin D; Vitamin D3	Drug: 2HRbZE/4HRb; Other Names: rifabutin-modified TB therapy; Drug: Vitamin D3
Experimental: CC-11050	Drug: 2HRbZE/4HRb; Other Names: rifabutin-modified TB therapy; Drug: CC-11050

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
SAEs and SUSARs	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).	through day 180

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
TEAEs other than SAEs and SUSARs	TEAEs other than SAEs, categorized according to severity, drug relatedness, and leading to early withdrawal.	through day 180
Sputum culture status on day 56	Proportion of patients with positive sputum cultures on solid culture medium after 8 weeks of treatment	day 56

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in FEV1 from baseline to 2 and 6 months	FEV1 (% of expected value)	days 56 and 180
18F-FDG PET/CT imaging (change from baseline to 2 months):	Maximum and mean standardized uptake values (SUV)	day 56
Serum neopterin	change from baseline b. CRP	day 56
Quantiferon gold in tube	change from baseline	day 56
Gene expression profiles (exploratory)	Change from baseline to 2 and 6 months in gene expression profiles	days 56 and 180
PD-1 expression (exploratory)	PD-1 expression on CD4 and CD8 lymphocytes	days 56 and 180

Collaborators and Investigators

• Sponsor: The Aurum Institute NPC
• Investigators: Principal Investigator: Robert S Wallis, MD,FIDSA, The Aurum Institute NPC

Publications and helpful links

General 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.

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2016
• Primary Completion (Actual): September 1, 2018
• Study Completion (Anticipated): December 1, 2020

Study Registration Dates

• First Submitted: September 8, 2016
• First Submitted That Met QC Criteria: November 17, 2016
• First Posted (Estimate): November 21, 2016

Study Record Updates

• Last Update Posted (Actual): January 10, 2019
• Last Update Submitted That Met QC Criteria: January 9, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Micronutrients; Anti-Bacterial Agents; Vitamins; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Antitubercular Agents; Phosphodiesterase Inhibitors; Antibiotics, Antitubercular; Phosphodiesterase 4 Inhibitors; Vitamin D; Cholecalciferol; Rifabutin; Everolimus; Auranofin; CC-11050
• Other Study ID Numbers: TBHDT-AUR1-8-178

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided