PanACEA DElpazolid Dose-finding and COmbination DEvelopment (DECODE) (DECODE)

• ClinicalTrials.gov Identifier: NCT04550832
• Recruitment Status: Active, not recruiting
• First Posted: September 16, 2020
• Last Update Posted: September 15, 2022
• Sponsor: LegoChem Biosciences, Inc
• Collaborators: Ludwig-Maximilians - University of Munich; Radboud University Medical Center; University of California, San Francisco
• Information provided by (Responsible Party): LegoChem Biosciences, Inc

Tracking Information

• First Submitted Date: September 1, 2020
• First Posted Date: September 16, 2020
• Last Update Posted Date: September 15, 2022
• Actual Study Start Date: October 22, 2021
• Estimated Primary Completion Date: December 30, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 10, 2020)

• Efficacy Endpoint : The change in sputum mycobacterial load [ Time Frame: week0 - week16 ]
  The change in sputum mycobacterial load given over 16weeks on treatment as qualified by a change in time to positive in BD MGIT 960® liquid culture described by non-linear mixed-effects methodology.
• primary Safety Endpoint : Proportion of patients experiencing adverse event as defined below [ Time Frame: week0 - week52 ]
  Proportion of patients experiencing expected oxazolidinone class toxicities, defined as peripheral or optical neuropathy, or incident leukopenia, anemia or thrombocytopenia, or adverse events in line with tyramine pressor response, all of Grade 2 or higher, possibly, probably or definitely related to DZD

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: September 10, 2020)

• Secondary safety endpoints : adverse event and as below [ Time Frame: week0 - week52 ]
  All adverse events Adverse events of Grade 3 severity or higher Adverse events possibly, probably or definitely related to study drugs Treatment discontinuations or interruptions related to adverse events/serious adverse events Frequency, severity and type of ECG alterations Changes in ECG intervals of PR, RR, QRS, QT, Fridericia-corrected QT [QTcF] Proportion of participants with QTcF > 500ms in ECGs on treatment Proportion of participants with a prolongation of QTcF > 60ms in ECGs relative to baseline measurement
• Secondary Efficacy Endpoints : Proportion of patients who suffer relapse and as below [ Time Frame: week0 - week52 ]
  Proportion of patients who suffer relapse, defined as recurrent disease caused by a strain identical to the baseline isolate, within 12 months post randomisation
• Secondary Efficacy Endpoints : out of patients completing 16 weeks of therapy and achieving stable culture conversion to negative (SCC) [ Time Frame: week8, week16 ]
  out of patients completing 16 weeks of therapy and achieving stable culture conversion to negative (SCC) as defined below by week 08, with no positives to follow by the week 16 visit. Time to recurrent TB, and to relapse, within 12 months post randomisation Time to stable sputum culture conversion (SCC) to negative on liquid media (defined as two negative cultures without an intervening positive culture). Time will be measured as time on treatment until the first negative culture. Proportion of participants who achieved SCC at each time point during treatment Proportion of participants with negative sputum culture on solid media at WK 08 and other timepoints Proportion of participants developing drug resistance among those not converting to negative culture

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: September 10, 2020)

• Mycobacteriology Identification and Characterization Endpoints [ Time Frame: Week8, Day 91 ]
  Minimum inhibitory concentrations (MIC) of BDQ, DLM, MXF, DZD, from a baseline isolate, and a representative isolate obtained at or after week8, if any Frequency of acquired mutations in the infecting strain over treatment assessed by whole genome sequencingComparison between bacterial strain causing recurrent disease, and the strain at baselineby whole genome sequencing, to discriminate relapse from re-infection
• Pharmacokinetic Endpoints : AUC 0-24 [ Time Frame: Day 14 ]
  Area under the plasma concentration curve from morning dosing to 24 hours (AUC 0-24) on day 14 (Week2)
• Pharmacokinetic Endpoints : The observed maximum concentration(Cmax) [ Time Frame: Day 14 ]
  Pharmacokinetic parameters will be assessed using non-compartmental techniques and non-linear mixed effects methodology.
• Pharmacokinetic Endpoints : Cmin [ Time Frame: Day 14 ]
  The minimum observed plasma concentration (Cmin) at day 14 (24 hours following the last dose for intake once daily (QD) and 12 hours following the last dose for twice daily intake (BID))
• Pharmacokinetic Endpoints : Apparent oral clearance (Cl/F) [ Time Frame: Day 14 ]
  Pharmacokinetic parameters will be assessed using non-compartmental techniques and non-linear mixed effects methodology.
• Pharmacokinetic Endpoints : Apparent volume of distribution (Vd/F) [ Time Frame: Day 14 ]
  Pharmacokinetic parameters will be assessed using non-compartmental techniques and non-linear mixed effects methodology.
• Pharmacokinetic Endpoints :Terminal half-life (t1/2) [ Time Frame: Day 14 ]
  Pharmacokinetic parameters will be assessed using non-compartmental techniques and non-linear mixed effects methodology.
• Exploratory endpoint : rate of change in MBLA [ Time Frame: week0 - week52 ]
  Rate of change in molecular bacterial load assay (MBLA) during treatment
• Exploratory endpoint : Time to stable culture conversion to negative in MBLA [ Time Frame: week0 - week16 ]
  Time to stable culture conversion to negative in MBLA (defined as two negative MBLAs without an intervening positive)
• Exploratory endpoint : Rate of change in bacterial load [ Time Frame: week0 - week16 ]
  Rate of change in bacterial load measured by quantification of sputum lipoarabinomannan (LAM) during treatment

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: PanACEA DElpazolid Dose-finding and COmbination DEvelopment (DECODE)
• Official Title: A Phase IIb, Open Label, Randomized Controlled Dose Ranging Multi-Center Trial to Evaluate the Safety, Tolerability, Pharmacokinetics and Exposure-Response Relationship of Different Doses of Delpazolid in Combination With Bedaquiline Delamanid Moxifloxacin in Adult Subjects With Newly Diagnosed, Uncomplicated, Smear-Positive, Drug-sensitive Pulmonary Tuberculosis
• Brief Summary: This trial is to describe the safety, tolerability and exposure-toxicity relationship of Depazolid given over 16 weeks, in combination with standard-dose Bedaquiline, Delamanid and Moxifloxacin, compared to standard-dose Bedaquiline, Delamanid and Moxifloxacin alone

Detailed Description

This will be an open label Phase IIb dose-finding, randomized, controlled study with a duration of 16 weeks of experimental therapy of Delpazolid(DZD) - Bedaquiline/Delamanid/ Moxifloxacin (BDM) in adult patients with newly diagnosed, smear positive, uncomplicated, drug sensitive pulmonary tuberculosis (TB) to evaluate the safety, efficacy, tolerability, pharmacokinetics and exposure/response-relationship of different doses of delpazolid in combination with bedaquiline, delamanid and moxifloxacin.

Participants will be randomized to one of five arms containing BDM standard dose with different doses of DZD.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Infections and Infestations
• Pulmonary Tuberculosis

Intervention

• Drug: Delpazolid
  Delpazolid is not licensed yet. Current experience in humans upto Phase IIA. Dose according to randomization to dosing arms 2-5.
  Other Name: LCB01-0371
• Drug: Bedaquiline, Delamanid, Moxifloxacin
  These three licensed drugs form the backbone of a new regimen to which delpazolid is added in arms 2-5.
  Other Name: BDM

Study Arms

• Active Comparator: Arm1(D0)

  Participants receive the following medication for the duration of 16weeks together with food.

  • Delpazolid : Will not administered
  • Bedaquiline: will be dosed as per the licensed dose: 400 mg orally once daily for the first 14 days, then 200 mg three times a week.
  • Delamanid: will be dosed as per the licensed dose: 200 mg orally twice daily doses of 100 mg.
  • Moxifloxacin: will be dosed as per the licensed dose: 400 mg orally once daily
  Intervention: Drug: Bedaquiline, Delamanid, Moxifloxacin
• Experimental: Arm2(D400)

  Participants receive the following medication for the duration of 16weeks together with food.

  • Delpazolid : Will be dosed 400 mg orally once daily
  • Bedaquiline: will be dosed as per the licensed dose: 400 mg orally once daily for the first 14 days, then 200 mg three times a week.
  • Delamanid: will be dosed as per the licensed dose: 200 mg orally twice daily doses of 100 mg.
  • Moxifloxacin: will be dosed as per the licensed dose: 400 mg orally once daily
  Interventions:

  • Drug: Delpazolid
  • Drug: Bedaquiline, Delamanid, Moxifloxacin
• Experimental: Arm3(D800-OD)

  Participants receive the following medication for the duration of 16weeks together with food.

  • Delpazolid : Will be dosed 800 mg orally once daily
  • Bedaquiline: will be dosed as per the licensed dose: 400 mg orally once daily for the first 14 days, then 200 mg three times a week.
  • Delamanid: will be dosed as per the licensed dose: 200 mg orally twice daily doses of 100 mg.
  • Moxifloxacin: will be dosed as per the licensed dose: 400 mg orally once daily
  Interventions:

  • Drug: Delpazolid
  • Drug: Bedaquiline, Delamanid, Moxifloxacin
• Experimental: Arm4(D1200)

  Participants receive the following medication for the duration of 16weeks together with food.

  • Delpazolid : Will be dosed 1200 mg orally once daily
  • Bedaquiline: will be dosed as per the licensed dose: 400 mg orally once daily for the first 14 days, then 200 mg three times a week.
  • Delamanid: will be dosed as per the licensed dose: 200 mg orally twice daily doses of 100 mg.
  • Moxifloxacin: will be dosed as per the licensed dose: 400 mg orally once daily
  Interventions:

  • Drug: Delpazolid
  • Drug: Bedaquiline, Delamanid, Moxifloxacin
• Experimental: Arm5(D800-BD)

  Participants receive the following medication for the duration of 16weeks together with food.

  • Delpazolid : Will be dosed 800 mg orally twice daily
  • Bedaquiline: will be dosed as per the licensed dose: 400 mg orally once daily for the first 14 days, then 200 mg three times a week.
  • Delamanid: will be dosed as per the licensed dose: 200 mg orally twice daily doses of 100 mg.
  • Moxifloxacin: will be dosed as per the licensed dose: 400 mg orally once daily
  Interventions:

  • Drug: Delpazolid
  • Drug: Bedaquiline, Delamanid, Moxifloxacin

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: September 13, 2022): 76
• Original Estimated Enrollment (submitted: September 10, 2020): 75
• Estimated Study Completion Date: March 30, 2024
• Estimated Primary Completion Date: December 30, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Provide written, informed consent prior to all trial-related procedures including HIV testing.
2. Male or female, aged between 18 and 65 years, inclusive.
3. Body weight between 40 and 90 kg, inclusive.
4. Newly diagnosed, previously untreated, drug susceptible pulmonary TB: presence of MTB complex and rapid molecular tests result confirming susceptibility to RIF and INH such as GeneXpert and/or HAIN MTBDR plus.
5. A chest X-ray (no older than 2 weeks) which, in the opinion of the Investigator, is consistent with TB.
6. Sputum positive on microscopy from concentrated sputum for acid-fast bacilli on at least one sputum sample (at least 1+ on the IUATLD/WHO scale).
7. The participant is willing to forgo consumption of foods high in tyramine for the period of taking study medication (See Appendix, section 20.2, page 92).

8. The participant is either unable to conceive/father children AND/OR his/her partner is unable to conceive/father children AND/OR they will consent to be using effective methods of contraception when engaging in heterosexual intercourse, as defined below:

   a. Non-childbearing potential: i. Female participant/sexual partner of male participant: Bilateral oophorectomy, and/or hysterectomy or bilateral tubal ligation more than 12 months ago and/or has been postmenopausal with a history of no menses for at least 12 consecutive months ii. Male participant/sexual partner of female participant: Vasectomised or has had a bilateral orchidectomy minimally three months prior to screening iii. Male participants having a pregnant female partner or a male sexual partner: At least one barrier method has to be used in this case. b. Effective contraception methods: i. Female participants: Two methods, including methods that the patient's sexual partner(s) use. At least one must be a barrier method. Contraception must be practised for at least until 12 weeks after the last dose of DZD. ii. Male participants: Two methods, including methods that the patient's female sexual partner(s) use. At least one must be a barrier method. Effective contraception must be ensured for at least 16 weeks after the last dose of DZD.

Note: hormone-based contraception alone may not be reliable when taking RIF during continuation phase; therefore, hormone-based contraceptives alone cannot be used by female participants/female partners of male participants to prevent pregnancy.

Exclusion Criteria:

1. Circumstances that raise doubt about free, unconstrained consent to study participation (e.g. prisoner or mentally handicapped person)
2. Poor general condition where delay in treatment cannot be tolerated or death within four months is likely.
3. Poor social condition which would make it unlikely that the patient would be able to complete follow-up
4. The patient is pregnant or breast-feeding.

5. The patient is infected with HIV with a CD4 count <220 cells/mm3. If >220 cells/mm3, patients will be included only if any of the following is applicable:

   • The patient is antiretroviral (ARV) naïve and able to postpone commencing HIV treatment for 2 months after the trial has started and then restrict regimens to those containing dolutegravir (see section 12.6.2 on ARVs) or The patient is ARV experienced (has been on ARV´s a minimum of 5 months) and able to switch to a dolutegravir-based regimen.
   • The patient is treated with nucleosidic reverse transcriptase inhibitors (are permitted as concomitant medication).
   • The patient is treated with protease inhibitors as part of antiretroviral treatment regimens, which will be stopped at least 3 days before the start of study treatment (WK01, day1) for a patient to be eligible.
   • The patient is treated with Efavirenz as part of antiretroviral treatment regimens which would have to be stopped 14 days before the start of study treatment (WK00, Day 01) for a patient to be eligible.
6. The patient has a known intolerance to any of the study drugs or concomitant disorders or conditions for which study drugs or standard TB treatment are contraindicated

7. The patient has a history of, or current evidence of clinically relevant cardiovascular metabolic, gastrointestinal, neurological, psychiatric or endocrine diseases, malignancy, or any other condition that will influence treatment response, study adherence or survival in the judgement of the investigator, especially:

   1. Neuropathy, or significant psychiatric disorder like depression or schizophrenia; especially if treatment for those has ever been required or is anticipated to be required
   2. Clinically significant evidence of extra-pulmonary TB (e.g. miliary TB, TB meningitis, but not limited lymph node involvement)
   3. Serious lung conditions other than TB, or significant respiratory impairment in the discretion of the investigator
   4. Any diabetes mellitus
   5. Cardiovascular disease such as myocardial infarction, heart failure, coronary heart disease, arrhythmia, tachyarrhythmia, or pulmonary hypertension
   6. Arterial hypertension (systolic blood pressure ≥140 mmHg and/or diastolic blood pressure of ≥90 mmHg on two occasions during screening).
   7. Long QT syndrome or family history of long QT syndrome or sudden death of unknown or cardiac-related cause
   8. Alcohol or other drug abuse that is sufficient to significantly compromise the safety or cooperation of the patient, that includes substances prohibited by the protocol or has led to significant organ damage at the discretion of the investigator.

8. Any of the following laboratory findings at screening:

   1. Serum amino aspartate transferase (AST) and/or alanine aminotransferase (ALT) >3x the upper limit of normal (ULN),
   2. Serum alkaline phosphatase or y-glutamyl transferase > 2.5x the ULN,
   3. Serum total bilirubin level >1.5x the ULN
   4. Estimated creatinine clearance (eCrCl; using the Cockroft and Gault formula [57] lower than 30 ml/min
   5. Serum albumin < 2.8 mg/dl
   6. Haemoglobin level <7.0 g/dl
   7. Platelet count <50,000/mm3
   8. Serum potassium below the lower level of normal for the laboratory
   9. Blood glucose at screening of less than 70mg/dL (3.9mmol/L)

9. ECG findings in the screening ECG: (one or more):

   1. QTcF of >0.450 s
   2. Atrioventricular (AV) block with PR interval > 0.20 s,
   3. QRS complex > 120 milliseconds
   4. Any other changes in the ECG that are clinically relevant as per discretion of the investigator

10. Restricted medication:

    1. Treatment with any other investigational drug within 1 month prior to enrolment or enrolment into other clinical (intervention) trials during participation.
    2. Previous anti-TB treatment with drugs active against MTB within the last 3 months prior to screening.

    3. Unable or unwilling to abide by the requirements regarding restricted medication or have taken restricted medication as described under section 12.6, page 58. Restricted medication includes the following drug classes:

       • Anti-TB drugs other than study drugs
       • Medication that lowers the threshold for epileptic seizures
       • Medication that prolongs the QTc interval
       • Drugs that affect monoaminooxidase or serotonin metabolism
       • CYP 450 inhibitors or inducers, including grapefruit containing foods / beverages and St. John's Wort

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: South Africa, Tanzania

Administrative Information

• NCT Number: NCT04550832
• Other Study ID Numbers: LCB01-0371-20-2-02; PanACEA-DECODE-01 ( Other Identifier: PanACEA )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Deidentified individual patient data, that underlie the results in published article(s) based on data from the trial which including text, tables, figures will be presented to various stakeholders. This reported will be presented to various stakeholder during various forums or meetings. First esults will be disclosed to participants, staff and our site Community Advisory Board. Thereafter we would invite several stakeholders from the community or visit their establishments to review study results. Simultaneously, the studying findings report will be sent to the various regulatory authorities, including the National Department of Health (NDoH). With NDoH and its divisions we will establish needs for further engagement and suggestions for policy or programmatic changes.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Time Frame: PD will be provided 1 - 2 years after and up to 5 years after the publication of the article on the results of the trial
• Access Criteria: IPD access will be provided for analyses of the related to the aims of research described in the protocol and for individual patient data meta analyses to researchers who provide a methodologically sound proposal to lcb_pv@legochembio.com

• Current Responsible Party: LegoChem Biosciences, Inc
• Original Responsible Party: Same as current
• Current Study Sponsor: LegoChem Biosciences, Inc
• Original Study Sponsor: Same as current

Collaborators

• Ludwig-Maximilians - University of Munich
• Radboud University Medical Center
• University of California, San Francisco

• Investigators: Not Provided
• PRS Account: LegoChem Biosciences, Inc
• Verification Date: September 2022