Patient case: 58-year-old female with endometrial cancer; genetic feature: PIK3R1

Clinical trial: Safety and Efficacy of Various Doses and Treatment Durations of Linezolid Plus Bedaquiline and Pretomanid in Participants With Pulmonary TB, XDR-TB, Pre- XDR-TB or Non-responsive/Intolerant MDR-TB (ZeNix)

Summary: To evaluate the efficacy, safety and tolerability of various doses and durations of linezolid plus bedaquiline and pretomanid after 26 weeks of treatment in participants with either pulmonary XDR-TB, pre-XDR-TB, or treatment intolerant or non-responsive MDR-TB.

Detailed description: A phase 3, multi-center, partially-blinded, randomized clinical trial in four parallel treatment groups. Bedaquiline and pretomanid treatment will not be blinded. Linezolid treatment dose and duration will be double-blinded.
  Participants will have a screening period of up to 14 days and will be randomized to receive one of the 4 active treatment arms. Participants will be randomized to one of the four regimens in a 1:1:1:1 ratio, using an interactive voice and web response system (IXRS) which will utilize a randomization system using stratification with a random element to allocate participants evenly across the arms by HIV status and type of TB.
  Each participant will receive 26 weeks of treatment. If participant's week 16 sputum sample is culture positive between the week 16 and week 26 treatment visits and their clinical condition suggests they may have an ongoing TB infection, Investigator may consider extending current treatment to 39 weeks. If the culture results between week 16 and week 26 are contaminated, missing or considered an isolated positive without clinical significance, available culture results should be used to make this decision. All decisions regarding treatment extension should be discussed with and approved by, in consultation with the Sponsor Medical Monitor before implementation.
  Participants will be followed for 78 weeks after end of treatment.

Eligibility: Inclusion Criteria:
  Participants are required to meet all of the following inclusion criteria during the screening period in order to be randomized.
  1. Provide written, informed consent prior to all trial-related procedures (including any additional consent required for participants considered as minors per applicable regulatory authority or ethics committee).
  2. Willingness and ability to attend scheduled follow-up visits and undergo study assessments.
  3. HIV testing (if an HIV test was performed within 1 month prior to screening, it should not be repeated as long as a documented result can be provided [ELISA and/or Western Blot and/or Electro-Chemiluminescence]. If HIV status is a confirmed known positive, repeated HIV test is not needed if ELISA and/or Western Blot and/or Electro-Chemiluminescence documentation of presence of HIV infection is available.
  4. Male or female, aged 14 years or older. (Male or female, aged 18 years or older in Moldova or Russia).
  Disease Characteristics:
  5. Participants with one of the following pulmonary TB conditions:
  a. XDR-TB with i. A documented culture positive or a molecular test positive (for MTB) from a sputum specimen collected within 3 months prior to screening or MTB confirmed in sputum based on molecular test within 3 months prior to or at screening and: ii. documented resistance to isoniazid, rifamycins, a fluoroquinolone AND an injectable during the current TB diagnosis/disease course any time prior to or during screening period (may be sensitive or resistant to isoniazid);
  b. Pre-XDR-TB with i. A documented culture positive or a molecular test positive (for MTB) from a sputum specimen collected within 3 months prior to screening or MTB confirmed in sputum based molecular test within 3 months prior to or at screening and; ii. documented resistance to rifamycins, and to a fluoroquinolone OR an injectable during the current TB diagnosis/disease course any time prior to or during screening period (may be sensitive or resistant to isoniazid);
  c. MDR-TB with i. documented by culture positive or a molecular test positive (for MTB) from a sputum specimen collected results within 3 months prior to screening or MTB confirmed in sputum based on molecular test within 3 months prior to or at screening and; ii. documented resistance to rifamycins, and to a fluoroquinolone OR an injectable during the current TB diagnosis/disease course any time prior to or during screening period (may be sensitive or resistant to isoniazid) and; iii. with documented non-response to treatment with the best available regimen for 6 months or more prior to enrollment who in the opinion of the Investigator have been adherent to treatment and will be adherent to study regimen.
  d. MDR-TB with i. documented by culture positive or a molecular test positive (for MTB) from a sputum specimen collected within 3 months prior to screening or MTB confirmed in sputum based on molecular test within 3 months prior to or at screening and: ii. documented resistance to isoniazid and rifamycins during the current TB diagnosis/disease course any time prior to or during screening period (may be sensitive or resistant to isoniazid) and; iii. who are unable to continue second line drug regimen due to a documented intolerance to:
  1. PAS, ethionamide, aminoglycosides or fluoroquinolones or;
  2. Current treatment not listed above that renders participant eligible for the study in the Investigator's opinion.
  6. Chest X-Ray within 6 months prior to or at screening, obtained and read locally by investigator or designee with results consistent with pulmonary TB in the opinion of the Investigator.
  Contraception:
  7. Be of non-childbearing potential or using effective methods of birth control, as defined below:
  Non-childbearing potential:
  1. Participant - not heterosexually active or practices sexual abstinence; or
  2. Female participant or male participant's female /sexual partner - bilateral oophorectomy, bilateral tubal ligation and/or hysterectomy or has been postmenopausal with a history of no menses for at least 12 consecutive months; or
  3. Male participant or female participant's male /sexual partner - vasectomised or has had a bilateral orchidectomy at least three months prior to screening.
  Effective birth control methods:
  1. Double barrier method which can include: a male condom, diaphragm, cervical cap, or female condom; or
  2. Female participant: Barrier method combined with hormone-based contraceptives or an intra-uterine device for the female participant;
  3. Male participant's female sexual partner: Double barrier method or hormone based contraceptives or an intra-uterine device for the female partner.
  And are willing to continue practicing birth control methods throughout treatment and for 6 months (female participants) and 12 weeks (male participants) after the last dose of study medication.
  Exclusion Criteria:
  Participants will be excluded from participation if they meet any of the following criteria during the screening period:
  Medical History and Concurrent Conditions
  1. Any condition in the Investigator's opinion (i.e., an unstable disease such as uncontrolled diabetes or cardiomyopathy, extra-pulmonary TB requiring extended treatment, cancer that could affect survival through the protocol-specified follow up period), where participation in the trial would compromise the well-being of participant or prevent, limit or confound protocol specified assessments.
  2. Abuse of alcohol or illegal drugs that in the opinion of the Investigator would compromise the participants' safety or ability to follow through with all protocol-specified restrictions, visits and evaluations.
  3. In the judgment of the Investigator, the patient is not expected to survive for more than 6 months.
  4. Karnofsky score < 60 at screening.
  5. History of allergy or known hypersensitivity to any of the trial Investigational Medicinal Products or related substances.
  6. Body mass index (BMI) < 17 kg/m2
  7. TB infection with historic DST or MIC results with values suggesting likely resistance to pretomanid, delamanid, linezolid or bedaquiline.; the Sponsor Medical Monitor must be consulted to help interpret any available historic results.
  8. Participants who, upon the evaluation of their pulmonary disease, are expected to require a surgical procedure.
  9. Having participated in other clinical studies with dosing of investigational agents within 8 weeks prior to screening or currently enrolled in an investigational study that includes treatment with medicinal agents. Participants who are participating in observational studies or who are in a follow up period of a trial that included drug therapy may be considered for inclusion.
  10. Participants with any of the following at Screening:
  -  QTcF interval on ECG >500 msec. Participants with QTcF > 450 must be discussed with and approved by the Sponsor Medical Monitor before enrollment. (Per measurements and reading done from screening central ECG.)
  -  Heart failure
  -  A personal or family history of congenital QT prolongation
  -  A history of or known, untreated, ongoing hypothyroidism
  -  A history of or ongoing bradyarrhythmia
  -  A history of Torsade de Pointe
  11. (Russia only) Participants with any of the following conditions where the use of linezolid is contraindicated:
  -  A history of thyrotoxicosis
  -  A history of uncontrolled arterial hypertension
  -  A history of pheochromocytoma
  -  A history of carcinoid syndrome
  -  A history of bipolar disorder
  -  A history of schizoaffective disorder
  12. Females who have a positive pregnancy test at Screening or already known to be pregnant, breast-feeding, or planning to conceive a child during the study or within 6 months of cessation of treatment. Males planning to conceive a child during the study or within 6 months of cessation of treatment.
  13. A peripheral neuropathy of Grade 3 or 4, according to DMID. Or, participants with a Grade 1 or 2 neuropathy which is likely to progress/worsen over the course of the study, in the opinion of the Investigator.
  14. (Russia only) Participants with lactose intolerance, lactase deficiency and/or glucose-galactose malabsorption.
  Previous and Concomitant Therapy
  15. Known (during screening) requirement for future Concomitant (during treatment) use of any prohibited and/or avoided medications noted in section 5.3.
  16. Prior use of Monoamine Oxidase Inhibitors (MAOIs) within 2 weeks of randomization.
  17. Prior use of serotonergic antidepressants within 3 days of randomization if Investigator foresees potential risks for serotonin syndrome when combined with linezolid.
  18. Participants who have received more than 2 weeks of bedaquiline, linezolid or delamanid prior to first dose of IMP.
  19. Participants with newly diagnosed tuberculosis and HIV that require initiation of appropriate HIV therapy before participant has received at least 2 weeks of an anti-tuberculosis regimen.
  20. HIV infected participants with planned continued use of zidovudine, stavudine, or didanosine. The antiretroviral therapy (ART) booster cobicistat should not be used.
  Diagnostic and Laboratory Abnormalities
  21. Participants with any of the following toxicities at Screening (labs may be repeated during screening period) as defined by the enhanced Division of Microbiology and Infectious Disease (DMID) adult toxicity table (November 2007):
  1. Viral load >1000 copies/mL (Unless newly diagnosed HIV and not yet on ART who otherwise qualify for participation);
  2. CD4+ count < 100 cells/µL (HIV positive participants);
  3. Serum potassium less than the lower limit of normal for the laboratory;
  4. Hemoglobin < 9.0 g/dL or 90g/L;
  5. Platelets <100,000/mm3 or < 100 x 10^9/L ;
  6. Absolute neutrophil count (ANC) < 1500/ mm3 or < 1.5 x 10^9/L;
  7. Aspartate aminotransferase (AST)
  -  Grade 3 or greater (> 3.0 x ULN) to be excluded;
  -  Results between 1.5 x ULN and 3 x ULN must be discussed with and approved by the Sponsor Medical Monitor
  8. Alanine aminotransferase
  -  Grade 3 or greater (> 3.0 x ULN) to be excluded;
  -  Results between 1.5 x ULN and 3 x ULN must be discussed with and approved by the Sponsor medical monitor;
  9. Total bilirubin
  -  greater than 1.5 x ULN to be excluded;
  -  1-1.5 x ULN must be discussed with and approved by the Sponsor Medical Monitor
  10. Direct bilirubin
  • Greater than ULN to be excluded
  11. Serum creatinine level greater than 1.5 times upper limit of normal
  12. Albumin <3.0 g/dl or < 30 g/L
  All inclusion and no exclusion criteria must be met. If no single variable/value is outside of the ranges of acceptability, but when multiple values are close to the limits and/or whenever the Investigator has reason to suspect that there might be a health problem (other than TB), enrolment should only be considered after discussing the case with the sponsor medical monitor.

Relevance to patient case: not relevant