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Protecting Households On Exposure to Newly Diagnosed Index Multidrug-Resistant Tuberculosis Patients (PHOENIx MDR-TB)

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ClinicalTrials.gov Identifier: NCT03568383
Recruitment Status : Recruiting
First Posted : June 25, 2018
Last Update Posted : October 15, 2019
Sponsor:
Collaborators:
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Otsuka Pharmaceutical Development & Commercialization, Inc.
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

Brief Summary:
The purpose of this study is to compare the efficacy and safety of 26 weeks of delamanid (DLM) versus 26 weeks of isoniazid (INH) for preventing confirmed or probable active tuberculosis (TB) during 96 weeks of follow-up among high-risk household contacts (HHCs) of adults with multidrug-resistant tuberculosis (MDR-TB) (index cases). High-risk HHCs are those with HIV or non-HIV immunosuppression, latent TB infection, and young children below the age of 5 years.

Condition or disease Intervention/treatment Phase
Tuberculosis, MDR Drug: Delamanid (DLM) Drug: Isoniazid (INH) Dietary Supplement: Pyridoxine (vitamin B6) Phase 3

Detailed Description:

This study will compare the efficacy and safety of 26 weeks of delamanid (DLM) versus 26 weeks of isoniazid (INH) for preventing confirmed or probable active tuberculosis (TB) during 96 weeks of follow-up among high-risk household contacts (HHCs) of adults with multidrug-resistant tuberculosis (MDR-TB) (index cases). High-risk HHCs are those with HIV or non-HIV immunosuppression, latent TB infection, and young children below the age of 5 years.

If at least one HHC within a household (HH) is found to be eligible, the HH will be randomized to one of the following:

Arm A: DLM daily for adults, adolescents, and children, given for 26 weeks.

Arm B: INH daily for adults, adolescents, and children, given for 26 weeks AND pyridoxine (vitamin B6) daily for adults, adolescents, and children, given for 26 weeks.

All high-risk HHCs in the same HH will receive the same randomized regimen.

All participants will be in the study for 96 weeks. At study entry, index cases will undergo a medical history review and sputum collection. HHCs will have study visits at study entry and at Weeks 2, 4, 8, 12, 16, 20, 26, 36, 48, 60, 72, 84, and 96. Visits may include physical examinations; blood, urine, and sputum collection; electrocardiograms (ECGs); and questionnaires and assessments. Forty HHCs under the age of 5 taking DLM will undergo an intensive PK visit at Week 8.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 5610 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Protecting Households On Exposure to Newly Diagnosed Index Multidrug-Resistant Tuberculosis Patients (PHOENIx MDR-TB)
Actual Study Start Date : June 3, 2019
Estimated Primary Completion Date : June 18, 2025
Estimated Study Completion Date : June 18, 2025

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Tuberculosis

Arm Intervention/treatment
Experimental: Arm A: Delamanid (DLM)
HHCs will receive delamanid (DLM) for 26 weeks.
Drug: Delamanid (DLM)

Adults and children ≥30 kg: delamanid 200 mg orally once daily.

Children ≥2.5 kg to <30 kg: weight-band dosing orally once daily as per the study protocol. As children gain weight, their DLM dose should be adjusted, typically every month or as the visit schedule permits.


Experimental: Arm B: Isoniazid (INH)
HHCs will receive isoniazid (INH) and pyridoxine (vitamin B6) for 26 weeks.
Drug: Isoniazid (INH)

Adults and children ≥24 kg: INH 300 mg orally once daily.

Children ≥2.5 kg to <24 kg: INH weight-band dosing orally once daily as per the study protocol. As children gain weight, their INH dose should be adjusted.


Dietary Supplement: Pyridoxine (vitamin B6)
All HHCs in Arm B must receive pyridoxine (vitamin B6) with each dose of INH based on the current local dosing guidelines. For children up to 3 years of age and nursing women, pyridoxine will be given as per local standard of care. Pyridoxine is not supplied through the study.




Primary Outcome Measures :
  1. Percent of participants with confirmed or probable active TB at any time between Day 0 and the week 96 study visit [ Time Frame: Measured through Week 96 ]
    TB diagnoses will be reviewed by the independent outcomes review committee to assess whether the HHC had TB, if it was confirmed or probable TB, and if it was MDR-TB.

  2. Percent of participants who permanently discontinue randomized study drug (DLM or INH) due to a treatment-related adverse event [ Time Frame: Measured through Week 96 ]
    Requiring discontinuation as defined in the protocol, or in the opinion of the site investigator is a treatment-limiting adverse event.


Secondary Outcome Measures :
  1. Percent of participants with confirmed active MDR-TB at any time between Day 0 and the week 96 study visit [ Time Frame: Measured through Week 96 ]
  2. Percent of participants who died from any cause at any time between Day 0 and 96 weeks of follow-up [ Time Frame: Measured through Week 96 ]
    Deaths will be reviewed by the independent outcomes review committee to assess whether the HHC had TB at the time of death, possibly undiagnosed, and relatedness of the death to TB.

  3. Percent of participants who died from any cause at any time between Day 0 and 96 weeks of follow-up, or with confirmed or probable active TB at any time between Day 0 and the week 96 study visit [ Time Frame: Measured through Week 96 ]
    Deaths and TB diagnoses will be reviewed by the independent outcomes review committee to assess whether the HHC had TB at the time of death, possibly undiagnosed, and relatedness of the death to TB; and whether the HHC had TB, if it was confirmed or probable TB, and if it was MDR-TB.

  4. Percent of participants with a Grade 3 or higher adverse event during the period receiving randomized study drug (DLM or INH) [ Time Frame: Measured through Week 26 ]
    If a HHC has a Grade 3 or higher adverse event prior to starting randomized study drug, then the same event will only be considered during follow-up if the grade worsens.



Information from the National Library of Medicine

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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

INDEX CASE

  • Men and women age greater than or equal to 18 years.
  • Pulmonary MDR-TB defined as:

    • Confirmation of rifampin/rifampicin (RIF) resistance and INH resistance by
    • adequate source documentation (including date of testing, test methodology, and test results) of RIF and INH resistance from a licensed/nationally approved* referral program, OR
    • if either or both results are unknown or not adequately documented (as noted above), then confirmation must be obtained using a DAIDS-approved laboratory that operates according to Good Clinical Laboratory Practices (GCLP) guidelines and participates in an appropriate external quality assurance (EQA) program.
    • *NOTE: The term "licensed/nationally approved" refers to a laboratory that has been certified or licensed by an oversight body within that country and approved for RIF and/or INH resistance testing.
    • NOTE: Pre-XDR and XDR TB are not exclusionary. See the A5300B/I2003B/PHOENIx MOPS for study-approved molecular and phenotypic methods.
  • Started MDR-TB treatment within the past 90 days.
  • Ability and willingness of the index case to provide informed consent to access the HH and approach HH members for evaluation.
  • HH of index case has at least one reported HHC.

HOUSEHOLD CONTACTS

If any member(s) of the HH is/are not eligible or do not want to participate, all other eligible TB contacts within the HH can still participate.

  • Currently lives or lived in the same dwelling unit or plot of land and shares or has shared the same housekeeping arrangements as the index case and who reports exposure within 90 days prior to the index case starting MDR-TB treatment. Also, shared greater than 4 hours of indoor airspace with the index case during any one-week period prior to the index case starting MDR-TB treatment.
  • HHCs must be in one of the following high-risk groups:

    • All children 0 to less than 5 years old at the time of enrollment regardless of tuberculin skin test (TST), interferon gamma release assay (IGRA), or HIV status;
    • Adults, adolescents, and children greater than or equal to 5 years of age who are TST-positive (greater than or equal to 5 mm) and/or IGRA-positive and whose HIV status is negative, indeterminate, or unknown, and who are not non-HIV immunosuppressed;
    • Adults, adolescents, and children greater than or equal to 5 years of age who are HIV-infected or are non-HIV immunosuppressed (defined as receiving anti-tumor necrosis factor (TNF) treatment, or being solid organ or hematologic transplant recipients), regardless of TST or IGRA status.
  • HIV-1 infection status must be documented as positive, negative, indeterminate or unknown for all HHCs. Unknown status includes those who previously tested HIV negative but the test was performed more than one year ago. HIV testing will be offered to all HHCs with negative of unknown status. For adults (18 years and older), HIV-1 infection must be documented by any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and confirmed by a licensed Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen or plasma HIV-1 RNA viral load greater than 1000 copies/mL. Two or more plasma HIV-1 RNA viral loads of greater than 1,000 copies/mL are also acceptable as documentation of HIV infection. More information is available on this criterion in the protocol.
  • The following specific laboratory values for infants, children, adolescents, and adults obtained within 30 days prior to study entry by any DAIDS-approved non-US laboratory that operates in accordance with GCLP and participates in appropriate external quality assurance programs.

    • Absolute neutrophil count (ANC) greater than or equal to 750 cells/mm^3
    • Hemoglobin greater than or equal to 7.4 g/dL
    • Platelet count greater than or equal to 50,000/mm^3
    • Creatinine less than or equal to 2 × upper limit of normal (ULN)
    • Potassium level greater than or equal to 3.0 mEq/L
    • Aspartate aminotransferase (AST) (SGOT) and alanine aminotransferase (ALT) (SGPT) less than or equal to 3 × ULN
    • Total bilirubin less than or equal to 2.5 × ULN (Note: if on atazanavir (ATV), total bilirubin greater than 2.5 x ULN is permitted if direct bilirubin less than or equal to 2.5 × ULN)
    • Albumin greater than 3 g/dL
    • NOTE: Participants with results from other laboratory tests that are outside the normal range may be eligible for the study, at the discretion of the site investigator, if not considered to be an obstacle to entry.
  • For females of reproductive potential, negative serum or urine pregnancy test within 7 days prior to study entry by any DAIDS-approved non-US laboratory that operates in accordance with GCLP and participates in appropriate external quality assurance programs.

    • NOTE: Reproductive potential is defined as:
    • Girls who have reached menarche or
    • Women who have had menses within the past 12 consecutive months and who do not have an FSH greater than 40 IU/L or
    • Women who have had menses within the past 24 consecutive months if an FSH measurement is not available
    • Women who have not undergone surgical sterilization (e.g., hysterectomy, or bilateral oophorectomy, or bilateral salpingectomy).
    • Female participants who are participating in sexual activity that could lead to pregnancy must agree to use one reliable form of contraceptive (i.e., hormonal contraceptive, condoms, IUD, diaphragm with spermicide, or cervical cap with spermicide) while receiving study treatments.
    • NOTE: Female participants who are not of reproductive potential, as defined above, or whose male partner(s) have undergone successful vasectomy with documented azoospermia or have documented azoospermia for any other reason, are eligible without requiring the use of contraceptives. Participant-reported history is acceptable documentation of menopause, hysterectomy, bilateral oophorectomy, or bilateral salpingectomy.
    • NOTE: Breast-feeding women may be enrolled. Their infants are not eligible for participation due to potential DLM transfer in breast milk.
  • For infants (0 to 1 year of age), weight greater than or equal to 2.5 kg at screening.
  • Ability and willingness of participant or legally-authorized representative (legal guardian or biological parent) to provide informed consent or assent as appropriate.
  • Chest radiograph without evidence of active TB performed within 70 days prior to study entry for HHCs greater than or equal to 2 years of age and within 30 days prior to study entry for HHCs less than 2 years of age.
  • QTcF interval less than or equal to 460 ms within 30 days prior to study entry as confirmed by the central ECG reading center.
  • Enrollment of the HHC within 30 days after the index case is enrolled. In the event that a HHC is suspected of having TB, then this window for enrollment may be extended from within 30 days to within 70 days to allow for TB testing of the HHC.

Exclusion Criteria:

INDEX CASE

  • Has previously enrolled into the A5300B/I2003B/PHOENIx trial as an index case or HHC, or is a member of a HH which has previously enrolled into the A5300B/I2003B/PHOENIx trial.

HOUSEHOLD CONTACTS

  • Current confirmed or probable or possible pulmonary or extrapulmonary TB, based on the following criteria: the current ACTG Diagnosis Appendix 100 for adults and for children of greater than or equal to 15 years of age; or the modified pediatric TB definitions for children less than 15 years of age as described in the A5300B/I2003B/PHOENIx MOPS.
  • Receipt of more than 30 cumulative days of INH, rifamycin, fluoroquinolone, or DLM in the 90 days prior to study entry.
  • History of or current liver cirrhosis at any time prior to study entry.
  • Evidence of acute hepatitis, such as abdominal pain, nausea and vomiting, jaundice, dark urine, and/or light stools within 90 days prior to study entry.
  • Peripheral neuropathy greater than or equal to Grade 2 within 90 days prior to study entry according to the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), corrected Version 2.1, July 2017.
  • Known allergy/sensitivity or any hypersensitivity to components of study drugs or their formulation.
  • Current cardiovascular disorder that is clinically relevant in the opinion of the site investigator, including but not limited to heart failure, coronary heart disease, second or third degree atrioventricular (AV) block, prolongation of the QRS complex over 120 ms (in both male and female participants), arrhythmia, or tachyarrhythmia.
  • Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
  • Serious illness requiring systemic treatment including parenteral therapy (e.g., antibiotics) and/or hospitalization within 30 days prior to study entry.
  • Currently receiving other medication with potential for adverse drug-drug interactions, including QT prolongation. Please see the study protocol for a list of prohibited medications.
  • Taken an investigational drug or vaccine within 30 days prior to study entry.
  • Has a clinical condition that in the site investigator's opinion would interfere with study participation.
  • Has enrolled into a TB vaccine or TB preventive therapy or TB therapeutic trial, including the A5300B/I2003B/PHOENIx trial, in the two years prior to study entry.
  • Not expected to be able to complete 96 weeks of study follow-up (e.g., seasonal or migrant workers or students who may not stay in the area).

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): NCT03568383


Locations
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Botswana
Gaborone CRS Recruiting
Gaborone, South-East District, Botswana
Contact: Tebogo J. Kakhu    267-3931353    tkakhu@bhp.org.bw   
Brazil
Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS Recruiting
Rio de Janeiro, Brazil, 21040-360
Contact: Sandra W. Cardoso, Ph.D., M.D.    55-21-22707064    sandra.wagner@ipec.fiocruz.br   
Haiti
GHESKIO Institute of Infectious Diseases and Reproductive Health (GHESKIO - IMIS) CRS Recruiting
Port-au-Prince, Haiti, HT-6110
Contact: Sandy N. Nerette, M.D.       snerette@gheskio.org   
Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR) CRS Recruiting
Port-au-Prince, Haiti, HT-6110
Contact: Cynthia Riviere, M.D.    509-22222241    criviere@gheskio.org   
Peru
Barranco CRS Recruiting
Lima, Peru, 15063
Contact: Helen B. Chapa    51-1-2067800 ext 209    hchapa@impactaperu.org   
San Miguel CRS Recruiting
Lima, Peru, 32-15088
Contact: Carla J. Porcile, R.N.    51-1-5621600 ext 644    cporcile@impactaperu.org   
Philippines
De La Salle Health Science Institute Angelo King Medical Research Center (DLSHSI-AKMRC) Recruiting
Cavite, Philippines, 4114
Contact: Maricelle S. Gler    63-9178230431    tarcelasg@yahoo.com   
South Africa
Soweto ACTG CRS Recruiting
Johannesburg, Gauteng, South Africa, 1862
Contact: Debra Peters    27-119899700    petersd@phru.co.za   
Wits Helen Joseph Hospital CRS (Wits HJH CRS) Recruiting
Johannesburg, Gauteng, South Africa, 2092
Contact: Anne Reyneke    27-11-2768817    areyneke@witshealth.co.za   
Durban International Clinical Research Site CRS Recruiting
Durban, Kwa Zulu Natal, South Africa, 4052
Contact: Rosie Mngqibisa, MB ChB, M.B.B.S.    27-31-2611093    mngqibisa@ecarefoundation.com   
PHRU Matlosana CRS Recruiting
Klerksdorp, North West Province, South Africa, 2574
Contact: Tumelo Moloantoa, MD    27-18-4653751    moloantoat@phru.co.za   
Rustenburg CRS Recruiting
Rustenburg, North West Province, South Africa, 0300
Contact: Tania Adonis    27-87-1351587    tadonis@auruminstitute.org   
Task Applied Science (TASK) CRS Recruiting
Cape Town, Western Cape Province, South Africa, 7530
Contact: Christelle v. Niekerk    27-21-9171044    christelle@task.org.za   
University of Cape Town Lung Institute (UCTLI) CRS Recruiting
Cape Town, Western Cape Province, South Africa, 7700
Contact: Catrien Drinkwater    27-21-4066850    catrien.drinkwater@uct.ac.za   
South African Tuberculosis Vaccine Initiative (SATVI) CRS Recruiting
Cape Town, Western Cape Province, South Africa, 7705
Contact: Chris Hikuam    27-21-4066228    chris.hikuam@uct.ac.za   
Tanzania
Kilimanjaro Christian Medical Centre (KCMC) Recruiting
Moshi, Tanzania
Contact: Cynthia A. Asiyo    255-753698484    cynthia.asiyo@duke.edu   
Thailand
Siriraj Hospital ,Mahidol University NICHD CRS Recruiting
Bangkok, Bangkoknoi, Thailand, 10700
Contact: Watcharee Lermankul    66-2-4197000 ext 5695    watchareeped@gmail.com   
Thai Red Cross AIDS Research Centre (TRC-ARC) CRS Recruiting
Pathumwan, Bangkok, Thailand, 10330
Contact: Parawee Thongpaeng    662-6523040 ext 106    parawee.t@hivnat.org   
Zimbabwe
Milton Park CRS Recruiting
Milton Park, Harare, Zimbabwe
Contact: Rachel Mahachi, M.Sc., R.N    263-24-2701356    rmahachi@uzchs-ctrc.org   
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Otsuka Pharmaceutical Development & Commercialization, Inc.
Investigators
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Study Chair: Gavin Churchyard, MBBCh MMed FRCP FCP(SA) PhD Aurum Institute
Study Chair: Amita Gupta, MD, MHS Johns Hopkins Medical Institutions, Center for Clinical Global Health Education
Study Chair: Anneke Hesseling, MD, PhD University of Stellenbosch
Study Chair: Susan Swindells, MBBS University of Nebraska

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Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT03568383     History of Changes
Other Study ID Numbers: A5300B/I2003B/PHOENIx
12041 ( Registry Identifier: DAIDS-ES Registry Number )
First Posted: June 25, 2018    Key Record Dates
Last Update Posted: October 15, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Individual participant data that underlie results in the publication, after deidentification.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Time Frame: Beginning 3 months following publication and available throughout period of funding of the AIDS Clinical Trials Group by NIH.
Access Criteria:
  • With whom?

    • Researchers who provide a methodologically sound proposal for use of the data that is approved by the AIDS Clinical Trials Group.
  • For what types of analyses?

    • To achieve aims in the proposal approved by the AIDS Clinical Trials Group.
  • By what mechanism will data be made available?

    • Researchers may submit a request for access to data using the AIDS Clinical Trials Group "Data Request" form at: https://actgnetwork.org/about-actg/templates-and-forms. Researchers of approved proposals will need to sign an AIDS Clinical Trials Group Data Use Agreement before receiving the data.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
Tuberculosis
Multidrug Resistance
Prevention
Household Contact
Additional relevant MeSH terms:
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Tuberculosis
Tuberculosis, Multidrug-Resistant
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Vitamins
Vitamin B 6
Pyridoxal
Pyridoxine
Vitamin B Complex
Isoniazid
Micronutrients
Nutrients
Growth Substances
Physiological Effects of Drugs
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents
Fatty Acid Synthesis Inhibitors
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents