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

NCT03888716 | Completed Phase 1

• 1 other identifier: KL1333 2018-102
• Study Type: interventional
• Target: 72
• Locations: 1 country
• Sites: 2

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.

Conditions

Mitochondrial Diseases; Mitochondrial Respiratory Chain Deficiencies; MELAS Syndrome; Mitochondrial Myopathies

Keywords

Mitochondrial Diseases; Mitochondrial Respiratory Chain Deficiencies; MELAS Syndrome; Mitochondrial Myopathies; Kearns-Sayre Syndrome; Ophthalmoplegia, Chronic Progressive External

Outcome Measures

Primary Outcomes (5)

• 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 Outcomes (10)

• 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

Other Outcomes (9)

• NAD+/NADH concentrations and ratio (part B and C)

  Days 10 and 15

• FGF21 and GDF15 concentrations (part B and C)

  Days 10 and 15

• Lactate/pyruvate concentrations and ratio (part B and C)

  Days 10 and 15

Study Arms (2)

KL1333

EXPERIMENTAL

25 and 100 mg KL1333 encapsulated tablets for daily oral dosing

Drug: KL1333

Matching placebo

PLACEBO COMPARATOR

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

Drug: Placebo Oral Tablet

Interventions

KL1333 DRUG

25 and 100 mg KL1333 encapsulated tablets

KL1333

Placebo Oral Tablet DRUG

25 and 100 mg placebo encapsulated tablets

Matching placebo

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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.
• 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.

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• Abliva AB: lead

Study Sites (2)

Covance Leeds

Leeds, West Yorkshire, LS2 9LH, United Kingdom

Location

UCL

London, United Kingdom

Location

MeSH Terms

Conditions

Mitochondrial Diseases; MELAS Syndrome; Mitochondrial Myopathies; Kearns-Sayre Syndrome; Ophthalmoplegia, Chronic Progressive External

Condition Hierarchy (Ancestors)

Metabolic Diseases; Nutritional and Metabolic Diseases; Mitochondrial Encephalomyopathies; Muscular Diseases; Musculoskeletal Diseases; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Cerebral Small Vessel Diseases; Cerebrovascular Disorders; Neuromuscular Diseases; Vascular Diseases; Cardiovascular Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Ophthalmoplegia; Ocular Motility Disorders; Cranial Nerve Diseases; Paralysis; Neurologic Manifestations; Eye Diseases; Retinitis Pigmentosa; Retinal Dystrophies; Retinal Degeneration; Retinal Diseases; Cardiomyopathies; Heart Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Signs and Symptoms

Study Officials

• Matilda Hugerth, MSc

  Abliva AB

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 19, 2019
• First Posted: March 25, 2019
• Study Start: March 18, 2019
• Primary Completion: March 16, 2021
• Study Completion: March 16, 2021
• Last Updated: October 20, 2021

Record last verified: 2021-10

Data Sharing

• IPD Sharing: Will not share

Locations

GB (2)