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A Phase I Study to Explore the Pharmacokinetics of Clofazimine in Combination with Three Antimicrobial Drugs in Japanese Patients with Pulmonary MABC Disease (MYCAT)

MYCAT (MYCAT)

10

The mean age of the 10 patients was 63.3 +/- 8.4 years. The cohort consisted of three males (30.0%) and seven females (70.0%). Regarding patient characteristics, nine patients (90.0%) had no relevant past medical history, while one patient (10.0%) did. Two patients (20.0%) had no comorbidities, and eight (80.0%) did. Nine patients (90.0%) had no drug allergies, and one (10.0%) had a history of drug allergy. Similarly, nine patients (90.0%) had not received prior treatment for pulmonary M. abscessus complex (MABC) disease, whereas one patient (10.0%) had. Subspecies identification of M. abscessus complex at screening revealed that M. massiliense was the most prevalent, found in eight patients (80.0%), followed by M. abscessus and M. abscessus/M. bolletii in one patient each (10.0%).

Of the 12 patients who provided informed consent for this clinical trial, 10 were enrolled. All 10 enrolled patients initiated treatment with the investigational drug. However, one patient discontinued the study on Day 12 due to an adverse event. The reason for discontinuation was QTcF prolongation (defined as a QTcF value of 450 msec or greater, or an increase of more than 60 msec from the baseline) observed at some point during the investigational drug administration. Two patients who provided consent were not enrolled. One patient was excluded because their 12-lead electrocardiogram (ECG) during the post-consent screening revealed a QTcF value exceeding 450 msec, meeting an exclusion criterion. The other patient did not meet the inclusion criteria and was screen-failed, as a positive M. abscessus complex result was not confirmed in their sputum culture at the time of screening.

Adverse events were reported in all 10 patients (100.0%) in the safety analysis set, with a total of 19 events. One patient (10.0%) experienced one QT prolongation-related event. Adverse events for which a causal relationship with the study drug could not be ruled out occurred in 8 patients (80.0%), totaling 15 events. No serious adverse events were observed. The most common adverse events were nausea and dysgeusia, each occurring in 5 patients (50.0%) with 5 events. Other events included increased aspartate aminotransferase (2 patients, 20.0%, 2 events), epigastric discomfort (1 patient, 10.0%, 1 event), vomiting (1 patient, 10.0%, 1 event), paresthesia (1 patient, 10.0%, 1 event), increased alanine aminotransferase (1 patient, 10.0%, 1 event), increased blood creatinine (1 patient, 10.0%, 1 event), electrocardiogram QT prolongation (1 patient, 10.0%, 1 event), and atrial fibrillation (1 patient, 10.0%, 1 event). Of these, the adverse events for which a causal relationship with the investigational drug could not be ruled out were: nausea (5 patients, 50.0%, 5 events), dysgeusia (4 patients, 40.0%, 4 events), increased aspartate aminotransferase (2 patients, 20.0%, 2 events), paresthesia (1 patient, 10.0%, 1 event), increased alanine aminotransferase (1 patient, 10.0%, 1 event), increased blood creatinine (1 patient, 10.0%, 1 event), and electrocardiogram QT prolongation (1 patient, 10.0%, 1 event). Regarding the known risks of clofazimine, specifically skin and gastrointestinal symptoms, no skin-related adverse events were reported in this trial. While gastrointestinal adverse events like nausea occurred in 5 patients, a causal relationship with clofazimine was ruled out in all cases.

- Primary Endpoint PK/PD analysis was conducted for adverse events that occurred in two or more patients for which a causal relationship could not be ruled out, namely liver function abnormalities, dysgeusia, and nausea. The results showed a tendency for a higher clofazimine trough concentration on Day 13 in patients with nausea compared to those without (P=0.088), but this difference was not statistically significant. No clear correlation was observed between the pharmacokinetic parameters (AUC and trough concentration) of clofazimine, clarithromycin, amikacin, imipenem/cilastatin and the occurrence of adverse events. - Secondary Endpoints 1) Adverse Events Adverse events occurred in all 10 patients (100.0%) in the safety analysis set, with a total of 19 events. One patient (10.0%) experienced a single QT prolongation-related event. A causal relationship with the study drug could not be ruled out for 15 adverse events that occurred in 8 patients (80.0%). No serious adverse events were observed. The breakdown of adverse events for which a causal relationship with the study drug could not be ruled out is as follows: nausea (5 patients, 50.0%, 5 events), dysgeusia (4 patients, 40.0%, 4 events), increased aspartate aminotransferase (2 patients, 20.0%, 2 events), paresthesia (1 patient, 10.0%, 1 event), increased alanine aminotransferase (1 patient, 10.0%, 1 event), increased blood creatinine (1 patient, 10.0%, 1 event), and ECG QT prolongation (1 patient, 10.0%, 1 event). 2) Change in QT Interval from Baseline 13 Days after Dosing The mean +/- standard deviation for the QTcF of patients in the safety analysis set was 434.29 +/- 11.70 msec at enrollment (N=10), 444.04 +/- 5.73 msec within 17 hours before starting clofazimine on Day 13 (N=9), and 441.52 +/- 6.32 msec 6 hours after clofazimine administration on Day 13 (N=9). The mean +/- standard deviation for the change in QTcF from baseline was 10.20 +/- 12.67 msec within 17 hours before starting clofazimine on Day 13 (N=9), and 7.68 +/- 10.99 msec 6 hours after clofazimine administration on Day 13 (N=9). One patient discontinued the study on Day 12 because their QTcF value reached 466.00 msec, meeting the discontinuation criterion (450 msec or greater). However, the change from baseline was 27.7 msec, which did not exceed the 60 msec threshold for discontinuation as specified by antiarrhythmic drug guidelines. For all other patients, the maximum change from baseline was 39 msec, which was not a concerning change. 3) Incidence of QT Prolongation-Related Events During the Dosing Period One QT prolongation-related event was observed in one of the 10 patients (10.0%) in the safety analysis set.

This study has clarified the pharmacokinetics and safety of clofazimine in Japanese patients with pulmonary M. abscessus complex (MABC) disease when used in combination with three other antibacterial agents. The findings can be considered useful evidence for future four-drug combination therapies.

No

https://jrct.mhlw.go.jp/latest-detail/jRCT2031220211

Ho Namkoong

Keio University Hospital

35 Shinanomachi, Shinjuku-ku Tokyo

hounamugun@keio.jp

Yasunori Osawa

Keio University Hospital

35 Shinanomachi, Shinjuku-ku Tokyo

+81-3-5315-4278

pm-group@ctr.hosp.keio.ac.jp

Complete

June. 01, 2022

Interventional

single arm study

open(masking not used)

uncontrolled control

single assignment

treatment purpose

(Selection criteria to be confirmed at the time of obtaining consent)
When obtaining consent, the investigator shall confirm the following 1) to 7) from the medical record, and confirm that the subject is able or willing to comply with 8) and 9).
1) The subject has obtained written consent from the patient himself/herself to participate in this clinical trial.
2) Japanese* patients with pulmonary MABC who meet the diagnostic criteria of the 2020 ATS/ERS/ESCMID/IDSA guideline.
*Japanese means the person/parents are Japanese nationals and the maternal and paternal grandparents are Japanese nationals.
3) Patients whose age at the time of obtaining consent is between 20 and 85 years old
4) Patients with clinical symptoms (sputum, cough, hemoptysis, chest pain, shortness of breath, fatigue, fever, night sweats, anorexia, weight loss, etc.) due to pulmonary MABC disease at the time of obtaining consent
5) Patients with imaging findings (bronchiectasis, granular shadows, small nodular shadows, cavernous lesions, infiltrative shadows, etc. on chest CT) due to pulmonary MABCS. Imaging findings should be confirmed by imaging taken within 6 months prior to the start of screening.
6) Must be able to take the study medication for the duration of the clinical trial.
7) No history of antimicrobial agents with antimicrobial activity against pulmonary MABC disease within 4 weeks prior to the start of screening
8) Patients who can be hospitalized for 16 days from the day before the start of treatment
9) Female patients of childbearing potential who agree to use contraception during the study period and for at least 4 months after the last dose of clofazimine

(Selection criteria to be confirmed during the screening period)
10) Patients with at least one positive sputum culture or bronchoscopic specimen culture within 6 months prior to screening and with a positive culture specimen at screening. If the pre-screening positive is confirmed by sputum culture, the patient must have been positive at least twice, and one of those times must have been confirmed within 6 months prior to screening.

1) Patients with a history of oral administration of clofazimine
2) Patients with a history of hypersensitivity to Lampren, clarithromycin, amikacin, or any component of imipenem hydrate or cilastatin sodium
3) Patients receiving drugs contraindicated in the most recent clarithromycin package insert including pimozide, ergotamine tartrate/caffeine anhydrous, isopropylantipirine, suvorexant, lomitapide mesylate, tadalafil(adcirca), ticagrelor, ibrutinib, ibabradine hydrochloride, venetoclax (in the dose escalation phase of relapsed or refractory chronic lymphocytic leukemia (including small lymphocytic lymphoma) during the dose-escalation phase), lurasidone hydrochloride, and anamorelin hydrochloride (contraindication to clarithromycin), etc.
4) Patients with hepatic or renal impairment who are receiving colchicine (contraindication to clarithromycin)
5) Patients with a history of hypersensitivity to aminoglycoside antibiotics or bacitracin (contraindication to amikacin)
6) Patients with hearing loss or other hearing impairment due to aminoglycoside antibiotics in the patient or a blood relative (contraindication to Amikacin in principle)
7) Patients receiving sodium valproate (contraindication to imipenem hydrate and cilastatin sodium)
8) Patients at risk of the following QT interval prolongation
(1) Patients with a history of torsade de pointe or other risk factors for heart failure
(2) Patients with hypokalemia requiring clinical consideration of treatment
(3) Patients with familial QT prolongation syndrome or a known family history of torsades de pointes
(4) Patients with an average QTcF greater than 450 msec measured 3 times at 5 plus or minus 1 minute intervals on a 12-lead ECG performed at screening
9) Patients receiving concomitant QT/QTc interval prolonging medications within 14 days prior to the start of treatment
10) Patients whose laboratory values at screening conflict with the following
(1) AST or ALT greater than or equal to 3 times the upper limit of the institutional reference value or total bilirubin greater than or equal to 2 times the upper limit of the institutional reference value
(2) eGFR (mL/min/1.73 m2) less than 30 mL/min
11) Patients with hearing loss or at risk of developing ototoxicity (deafness) due to concomitant medication (amikacin) [Patients should be referred to an otorhinolaryngologist if an abnormal hearing test (250-8000 Hz using air conduction) is detected during screening and an otorhinolaryngologist has confirmed that the patient has hearing loss or that the concomitant medication ( The patient should be excluded if an otolaryngologist determines that the patient has hearing loss or that ototoxicity (hearing loss) may occur with the use of concomitant medication (amikacin).
12) Patients with respiratory depression due to neuromuscular weakness, etc., who are judged by the investigator to have problems participating in the study.
13) Patients with a history of active primary, metastatic or other malignancy requiring treatment within 1 year prior to screening. (unless the malignancy is intraepithelial or has been cured by surgery or other treatment and the risk of recurrence is judged to be very low).
14) Patients with positive HIV antibody, HCV antibody, HBs antigen, HBs antibody, or HBc antibody at screening (however, even if the HBs antibody or HBc antibody test is positive, the patient may be included only if the HBV-DNA is measured and negative at the physician's discretion.)
15) Women with a positive pregnancy test or who are breastfeeding
16) Patients with complications that affect absorption of oral intake (e.g., malabsorption syndrome) and whose absorption of the study drug and concomitant medications (oral drugs) is determined by the investigator to be affected.
17) Patients who are currently abusing alcohol, drugs, or illegal drugs
18) Patients who are otherwise judged by the investigator to have problems participating in the study.

Both

Japanese Patients with Pulmonary MABC Disease

After obtaining consent from the subject, a screening test will be performed. After eligibility is confirmed, enrollment will be conducted and the combination of clofazimine and clarithromycin, amikacin, and imipenem hydrate/cilastatin sodium will be initiated.

In the screening phase, observations and examinations for eligibility confirmation and baseline data acquisition will be conducted after consent is obtained.
During the study drug administration phase, all subjects will be managed as inpatients throughout the study period (at least from the day before Day 1 to Day 14), and blood samples for PK study will be collected from Day 1 to Day 2 (up to 24 hours after Day 1 administration) and from Day 13 to Day 14 (up to 24 hours after Day 13 administration). If the investigational drug is discontinued, blood samples for PK study should be collected from the day of the last dose to the day after the last dose (up to 24 hours after the last dose), if possible. Blood sampling should be performed immediately before and 2, 4, 6, 8, 12, and 24 hours after administration of clofazimine on Day 1 and Day 13 (or the last dosing day). Clarithromycin and amikacin should be started at the same time if possible, and imipenem hydrate and cilastatin sodium should be started after the completion of amikacin infusion. If for some reason it is not possible to start clofazimine and clarithromycin and amikacin at the same time, the reason and the exact time of administration of each drug (start and end time for imipenem) should be recorded on the source documents. In addition, 12-lead ECG should be measured on Day 1 and Day 13 (or the last day of administration) for PD study. If the investigational drug is discontinued, measurements will be taken on the last day of administration whenever possible.Dosage and administration of each drug are as follows
Clofazimine: clofazimine 100 mg orally once daily immediately after meals (100 mg/day)
Clarithromycin: 400 mg orally twice daily (800 mg/day)
Amikacin: 15 mg/kg once daily for 30 plus 15 min IV infusion if eGFR 60 mL/min or higher (15 mg/kg/day)
If eGFR 40 mL/min or greater and less than 60 mL/min, 7.5 mg/kg once daily for 30 plus 15 minutes intravenous infusion (7.5 mg/kg/day)
If eGFR 30 mL/min or greater and less than 40 mL/min, 4 mg/kg once daily over 30 plus 15 minutes IV infusion (4 mg/kg/day)
Imipenem hydrate/cilastatin sodium: if eGFR 60 mL/min or greater, 1 g administered intravenously over 30 minutes 3 times daily (3 g/day)
If eGFR 30 mL/min or greater and less than 60 mL/min, 0.5 g administered intravenously over 30 minutes 3 times a day (1.5 g/day)

Japanese Patients with Pulmonary MABC Disease

PK/PD of clofazimine and clarithromycin, amikacin, imipenem hydrate and cilastatin sodium

Adverse Events
Change from baseline in QT time at 13 days after initiation of treatment
Frequency of QT prolongation related events during the treatment period

+81-3-5363-3848

Mar. 31, 2022

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