Mitochondrial Diseases
Conditions
Brief summary
The purpose of this study is to investigate if the study medicine, KL1333, is safe, well-tolerated and effective long-term in improving the symptoms of fatigue and impacts on daily living and functional capacity (physical abilities) in people with PMD.
Detailed description
This is a 12-month open-label extension (OLE) study to evaluate the safety, tolerability, and efficacy of KL1333 in subjects previously treated with KL1333 or placebo in Study KL1333-2020-104A (hereafter referred to as FALCON). Subjects can be enrolled in this extension study either directly at the FALCON study completion visit (FALCON Week 48) or the safety follow-up visit (FALCON Week 53) or later in time. Subjects who previously received KL1333 in FALCON will receive retreatment whereas subjects previously treated with placebo will be treatment naïve to KL1333. The study consists of a screening visit (if the subject rolls over directly from the FALCON study completion visit \[FALCON Week 48\] or the safety follow up visit \[FALCON Week 53\], the screening visit is coincident with the visit), a 48-week treatment course with KL1333 up to 100 mg/day, a completion visit (end of treatment; EoT) and approximately 5 weeks of follow up, including the end of study (EoS) visit. The treatment period may extend beyond 48 weeks until the study drug is commercially or otherwise available, in which case the EoT visit will occur later than Week 48. Periodic safety monitoring visits (phone visits every 4 weeks after Week 48 and clinic visits every 24 weeks after Week 48) will continue for subjects who receive KL1333 in the optional extended treatment period until the study drug is commercially or otherwise available.
Interventions
DRUGNapazimone
Product: KL1333 (international nonproprietary name: napazimone) Dose: Each subject will be up-titrated to his/her maximum well tolerated dose. The starting dose will be 25 mg KL1333 twice daily (BID; total daily dose of 50 mg). If KL1333 is considered to be well tolerated after 4 weeks of treatment, the dose will be increased to 50 mg KL1333 BID (total daily dose of 100 mg). The dose may be lowered from 50 mg BID to 25 mg BID at the investigator's discretion throughout the study in case of tolerability issues. Frequency: Twice daily Route: Oral
Sponsors
Pharming Technologies B.V.
ICON plc
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Open-label Extension
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Completed the FALCON study (age 18 years or older), and in the opinion of the investigator and sponsor has been compliant with the study requirements * Willingness and ability to attend study appointments within the specified time windows * Willingness and ability to complete electronic patient-reported outcomes * Concomitant medications likely to remain stable throughout participation in the study where clinically possible * Willingness to suspend treatment with idebenone during the study
Exclusion criteria
* The subject is, in the investigator's opinion, unlikely to comply with the protocol, e.g., due to cognitive impairment, or is unsuitable for any reason. * Any medical, psychiatric, laboratory or other condition that may negatively affect the benefit-risk considerations of study participation or interfere with the interpretation of study results and, in the judgment of the investigator and/or the medical monitor, would make the subject inappropriate for entry into this study. Subjects not enrolling directly at the FALCON study completion visit (FALCON Week 48) or the safety follow-up visit (FALCON Week 53) study will be required to fulfill the additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adverse events | Through study at least for 48 weeks | Number of adverse events will be monitored throughout the study for all subjects |
| Physical examination | At Baseline Week 0, Week 4, Week 24 and Week 48 | The following parameters and body systems will be examined and any abnormalities described: height and weight; general appearance; skin; head, ears, eyes, nose, and throat; lungs; heart; lower extremity examination; abdomen; neurologic and lymph nodes. Any clinically significant changes from baseline should be recorded as AEs. |
| Vital signs | At Baseline Week 0, Week 4, Week 24 and Week 48 | Body temperature, systolic and diastolic cuff blood pressure, pulse rate and pulse oximetry will be measured and any clinically significant changes from baseline should be recorded as AEs. |
| Electrocardiogram | At Baseline Week 0, Week 4, Week 24 and Week 48 | Changes from baseline of ECG parameters will be evaluated. |
| Safety laboratory - blood chemistry | At Baseline Week 0, Week 4, Week 24 and Week 48 | Monitoring of the clinically significant laboratory results for sodium, potassium, chloride, bicarbonate/carbon dioxide;, blood urea nitrogen, serum creatinine, glucose, albumin, total protein, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, total bilirubin, direct bilirubin, indirect bilirubin, calcium, gamma-glutamyl transferase, creatine kinase |
| Safety laboratory - urinalysis | At Baseline Week 0, Week 4, Week 24 and Week 48 | Monitoring of the clinically significant laboratory results for specific gravity, pH, semi-quantitative "dipstick" evaluation of glucose, protein, bilirubin, ketones, leukocytes, blood microscopy and/or culture to be performed if clinically indicated or if urinalysis results positive. |
| Safety laboratory - hematology | At Baseline Week 0, Week 4, Week 24 and Week 48 | Monitoring of the clinically significant laboratory results for Hemoglobin, hematocrit, white blood cell with differentials (monocytes, eosinophils, basophils, neutrophils, lymphocytes) as an absolute value, red blood cell count, platelet count, C-reactive protein |
| Occurence of metabolic decompensation and lactic acidosis or image-verified stroke-like episodes consequent to GI AE and AESIs | Through study at least for 48 weeks | These events will be monitored throughout the study. |
| Columbia Suicide Severity Rating Scale (C-SSRS) | At Baseline Week 0 | C-SSRS assesses suicidal ideation and behavior risk through a series of questions to assess for suicidal ideation and behavior, the severity and immediacy of the risk, and the level of support the subject may need. C-SSRS Severity of Ideation scores of 4 or 5 are considered SAEs. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Patient-reported mitochondrial fatigue | Through study at least for 48 weeks | Patient-Reported Outcomes Measurement Information System® Fatigue PMD short form. The PROMIS® Fatigue PMD short form consists of 9 items. Each item has numerical rating scale (NRS) response options consisting of never (1), rarely (2), sometimes (3), often (4), and always (5). |
| Functional outcome | At Baseline Week 0, Week 4, Week 24 and Week 48 | 30 seconds sit-to-stand test |
| Patient-reported lower extremity function | At Baseline Week 0, Week 4, Week 12, Week 24, Week 36 and Week 48 | Neuro-QOL Lower Extremity Function (Mobility) - short form. It is a reliable and validated brief 8-item survey of one's ability to carry out various activities involving the lower limb/trunk region and increasing degrees of bodily movement. Each item has numeric rating scale (NRS) response options consisting of Without any difficulty (5), With a little difficulty (4), With some difficulty (3), With much difficulty (2), and unable to do (1). |
| Other patient-reported outcome - Patient Global Impression (multiple) | At Baseline Week 0, Week 4, Week 12, Week 24, Week 36 and Week 48 | The Patient Global Impression of Severity is rated on a 4-point NRS, assessed on a scale ranging from 1 (none) to 4 (severe) for severity. The Patient Global Impression of Change is rated on a 5-point numeric rating scale (NRS), with the change from baseline assessed on a scale ranging from 2 (much better) to -2 (much worse), with 0 indicating no change from baseline. |
| Other patient-reported outcomes - 5-level EuroQol-5 Dimension | At Baseline Week 0, Week 4, Week 12, Week 24, Week 36 and Week 48 | The EQ-5D-5L includes items addressing mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The scale yields a single score on a 0 to 100 scale. |
| Global impression of severity of PMD disease expression | At Baseline Week 0, Week 24 and Week 48 | Clinician Global Impression of PMD - severity and change |
| Assessments of mitochondrial disease progression | At Baseline Week 0, Week 24 and Week 48 | Newcastle Mitochondrial Disease Adult Scale, Subscales I-III |
| Mitochondrial diabetes, subgroup analysis | At Baseline Week 0, Week 24 and Week 48 | Glycated hemoglobin (HbA1c, in subjects with diabetes) |
Countries
Belgium, Czechia, Denmark, France, Germany, Italy, Netherlands, Spain, United States
Contacts
CONTACTAudrey Simon, Sr. CPM
Outcome results
None listed