A Phase Ia/Ib, SAD and MAD Study of of KL1333 in Healthy Subjects and Patients With Primary Mitochondrial Disease

Sponsor

Abliva AB (Industry)

Overall Status

Completed

CT.gov ID

NCT03888716

Collaborator

(none)

Enrollment

Locations

Arms

Actual Duration (Months)

Patients Per Site

1.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This will be a double blind, randomised, placebo controlled, single and multiple oral dose study conducted in 3 parts: Part A, Part B and Part C. Part A and Part B include healthy volunteers only and will be completed before Part C including patients with primary mitochondrial disease will be initiated. The starting dose in the first cohort of Part A will be 25 mg. The dose level in the additional cohorts will be decided following review of data of the previous cohorts.

Condition or Disease	Intervention/Treatment	Phase
Mitochondrial Diseases Mitochondrial Respiratory Chain Deficiencies MELAS Syndrome Mitochondrial Myopathies	Drug: KL1333 Drug: Placebo Oral Tablet	Phase 1

Detailed Description

Part A: Eight healthy subjects will be studied in a single cohort (Group A1). Potential subjects will be screened to assess their eligibility to enter the study within 28 days prior to the first dose administration. Subjects will participate in 2 treatment periods, fasting or after consuming a standard high-fat breakfast. For each treatment period, subjects will reside at the Phase I clinical site from Days 1 to 3 (48 hours postdose). Subjects will return to the clinical site for outpatient visits on Days 4 and 5. There will be at least a 10 day washout between doses Additional single-dose cohorts may be enrolled based on data obtained from either Parts A or B.

Part B: Sixteen healthy subjects will be studied in 2 cohorts (Groups B1 and B2), with each cohort consisting of 8 subjects. Following review of safety, tolerability, and PK data, up to 3 additional dose cohorts of healthy subjects may be added to further explore the PK, safety, and tolerability of KL1333. Potential subjects will be screened to assess their eligibility to enter the study within 28 days prior to the first dose administration. All subjects will participate in 1 treatment period and will reside at the Phase I clinical site from Days -1 to 12 (48 hours post final dose). Subjects will return to the clinical site for outpatient visits on Days 13 and 14. On Day 1, 6 subjects will be randomised to receive KL1333 and 2 subjects will be randomised to receive placebo. Subjects will return for a Follow-up visit on Day 15, 5 days after their final dose.

Part C: A total of 8 patients diagnosed with any mitochondrial disease will be enrolled in this part of the study. Part C may start after the dose selection conference has been completed for the final cohort of Part B, at a daily dose no higher than the highest well-tolerated dose in Part B. Potential study patients will be screened to assess their eligibility to enter the study within 35 days prior to the first dose administration. Patients will reside at the clinical site from Days -1 to 2 and Days 10 to 11 and return to the clinical site for outpatient visits on Days 4 and 8. It is planned for patients to receive study drug once daily on Days 1 to 10. Patients will return for a Follow-up visit on Day 15, 5 days after their final dose.

Study Design

Study Type:

Interventional

Actual Enrollment :

72 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

A Phase Ia/Ib, Multiple-site Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of KL1333 After a Single and Multiple Ascending Oral Doses in Healthy Subjects and Patients With Primary Mitochondrial Disease

Actual Study Start Date :

Mar 18, 2019

Actual Primary Completion Date :

Mar 16, 2021

Actual Study Completion Date :

Mar 16, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: KL1333 25 and 100 mg KL1333 encapsulated tablets for daily oral dosing	Drug: KL1333 25 and 100 mg KL1333 encapsulated tablets
Placebo Comparator: Matching placebo 25 and 100 mg KL placebo encapsulated tablets for daily oral dosing	Drug: Placebo Oral Tablet 25 and 100 mg placebo encapsulated tablets

Arm

Intervention/Treatment

Experimental: KL1333

25 and 100 mg KL1333 encapsulated tablets for daily oral dosing

Drug: KL1333

25 and 100 mg KL1333 encapsulated tablets

Placebo Comparator: Matching placebo

25 and 100 mg KL placebo encapsulated tablets for daily oral dosing

Drug: Placebo Oral Tablet

25 and 100 mg placebo encapsulated tablets

Outcome Measures

Primary Outcome Measures

Safety: incidence and severity of AEs [Day 15]
Safety: incidence of laboratory abnormalities, based on haematology, clinical chemistry, and urinalysis test results [Day 15]
Safety: 12 lead ECG parameters [Day 15]
Safety: Number of participants with clinically significant abnormal vital signs measurements [Day 15]
Safety: Number of participants with clinically significant abnormal physical examinations [Day 15]

Secondary Outcome Measures

PK: area under the curve, AUC0 ∞ [Day 1]
PK: AUC over a dosing interval (AUC0 τ) [Days 1 and 10]
PK: temporal change parameter (TCP; AUC0 τ/AUC0-∞) [Days 1 and 10]
PK: Cmax [Day 1]
PK: time of the Cmax (Tmax) [Day 1]
PK: minimum observed plasma concentration (Cmin) [Days 1 and 10]
PK: apparent plasma terminal elimination half life (t1/2) [Days 1 and 10]
PK: mean residence time (MRT) [Days 1 and 10]
PK: apparent total plasma clearance (CL/F) [Days 1 and 10]
PK: apparent volume of distribution during the terminal phase (Vz/F) [Days 1 and 10]

Other Outcome Measures

NAD+/NADH concentrations and ratio (part B and C) [Days 10 and 15]
Biomarker
FGF21 and GDF15 concentrations (part B and C) [Days 10 and 15]
Biomarker
Lactate/pyruvate concentrations and ratio (part B and C) [Days 10 and 15]
Biomarker
Newcastle Mitochondrial Disease Adult Scale (NMDAS) (part C) [Day 10]
Assessment of mitochondrial disease. The NMDAS is a validated clinical rating scale designed to capture the natural history of mitochondrial disease. The NMDAS includes 3 domains: current function, system specific involvement, and current clinical, assessed on 6-point Likert-type scale from 0 to 5, as well as a fourth section including a score for the 12-Item Short Form Survey-Version 2.
Clinician Global Impression (CGI) (part C) [Day 10]
Assessment of illness severity, global improvement or change, and therapeutic response.The CGI is a 3-item observer-rated scale that measures illness severity, global improvement or change, and therapeutic response. The CGI is rated on a 7-point Likert-type scale, with the severity of illness scale using a range of responses from 1 (normal) to 7 (amongst the most severely ill patients).
Patient Global Impression-Improvement (PGI-I) (part C) [Day 10]
Patient reported assessment of severity of illness. The PGI-I is a patient-rated scale using a 7-point Likert-type scale, with the severity of illness scale using a range of responses from 1 (normal) to 7 (amongst the most severely ill patients). An item about the patient's worst symptom will be included in the assessment for this study.
Daily Fatigue Impact Severity (D-FIS) (part C) [Day 10]
Assessment of fatigue. The D-FIS is a patient-rated scale developed to assess the symptom of fatigue as part of an underlying chronic disease or condition. The D-FIS includes 8 items assessed on 5-point Likert-type scale from 0 (no problem) to 4 (extreme problem).
Quality of Life in Neurological Disorders Fatigue Scale (Neuro-QoL Fatigue) (part C) [Day 10]
Assessment of fatigue. The Neuro-QoL Fatigue is one of several scales that make up the Quality of Life in Neurological Disorders measurement system. It is a reliable and validated brief 19-item survey of fatigue, completed by the subject, with a recall period of the past 7 days. The 19 items are scored from 1 (never) to 5 (always) and consequently, Neuro-QoL Fatigue total scores range from 19 to 95, with higher scores indicating greater fatigue and greater impact of mitochondrial disease on activities.
30 Second Sit-to-Stand Test (part C) [Day 10]
Test

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria (selected):

Healthy subjects and patients with mitochondrial disease must satisfy all of the following criteria at the Screening visit unless otherwise stated:

Females will not be pregnant or lactating, and females of childbearing potential and males will agree to use contraception.
Able to comprehend and willing to sign an ICF and to abide by the study restrictions.
Able to perform all protocol-specified assessments and comply with the study visit schedule.

Additional inclusion criteria for healthy subjects:

Males or females, of any race, between 18 and 65 years of age, inclusive.
Weight ≥50 kg and body mass index between 18.0 and 32.0 kg/m2, inclusive.
In good health, determined by no clinically significant findings from medical history, physical examination, 12 lead ECG, vital signs measurements, and clinical laboratory evaluations (congenital nonhaemolytic hyperbilirubinemia [eg, Gilbert's syndrome] is not acceptable) at Screening and Check in as assessed by the Investigator.

Additional inclusion criteria for patients with mitochondrial disease:

Males or females, of any race, between 18 and 75 years of age, inclusive.
Body mass index between 15.0 and 32.0 kg/m2, inclusive.
Any mitochondrial disease that has been genetically confirmed.
Clinically stable, apart from symptoms associated with the diagnosis of mitochondrial disease, as determined by medical history, physical examination, 12 lead ECG, vital signs measurements, and clinical laboratory evaluations at Screening and Check-in as assessed by the Investigator.

Exclusion Criteria (selected):

Healthy subjects and patients with mitochondrial disease will be excluded from the study if they satisfy any of the following criteria at the Screening visit unless otherwise stated:

History of significant hypersensitivity, intolerance, or allergy to any drug compound, food, or other substance, including KL1333 or its excipients, unless approved by the Investigator.
History of gastroesophageal reflux disease, gastric erosions, peptic ulcer disease, or gastrointestinal bleeding episodes.
History of stomach or intestinal surgery or resection that would potentially alter absorption and/or excretion of orally administered drugs including cholecystectomy (uncomplicated appendectomy and hernia repair will be allowed).
History of malignancy of any organ system other than localised basal cell carcinoma of the skin, treated or untreated, within 5 years prior to Screening, regardless of whether there is evidence of local recurrence or metastases.
History of clinically significant illness (except for mitochondrial disease in the patients in Part C) or surgery within 4 weeks prior to Screening, as determined by the Investigator.
History of alcoholism or drug/chemical abuse within 2 years prior to Screening.
Alcohol consumption of >28 units per week for males and >21 units per week for females. One unit of alcohol equals ½ pint (285 mL) of beer or lager, 1 glass (125 mL) of wine, or 1/6 gill (25 mL) of spirits.
Positive alcohol breath test result or positive urine drug screen (confirmed by repeat) at Screening or Check in.
Positive hepatitis panel and/or positive human immunodeficiency virus test

Additional exclusion criteria for patients with mitochondrial disease:

Use of idebenone or medications (prescription or nonprescription) that have effects on metabolism or unknown binding sites (eg, vitamin E, co-enzyme 10, arginine) within 35 days or 5 half-lives, whichever is longer, prior to the first dose.
Use of prescription drugs within 14 days prior to dosing, with the exception of established therapy for mitochondrial disease and the treatment of associated disorders that has been stable for at least 7 days prior to the first dose, as approved by the Medical Monitor and Investigator, in consultation with the Sponsor.
Uncontrolled diabetes mellitus, as determined by the Investigator. Creatinine clearance <45 mL/min as calculated by the Cockcroft-Gault equation