A Dose-escalating Clinical Trial With KH176

Phase 1

Completed

Conditions: LHON
MELAS
Leigh Syndrome
Mitochondrial Disease
Mitochondrial DNA tRNALeu(UUR) m.3243A<G Mutation

Interventions: Drug: KH176
Drug: placebo

Registration Number: NCT02544217

Lead Sponsor: Khondrion BV

Brief Summary: Mitochondrial Diseases are rare progressive, multi-system, often early fatal disorders affecting both children and adults. KH176 is a novel chemical entity currently under development for the treatment of inherited mitochondrial diseases, including MELAS (Mitochondrial Encephalomyopathy, Lactic acidosis, and Stroke-like episodes), Leigh's Disease and Leber's Hereditary Optic Neuropathy (LHON). KH176 is a potent intracellular redox modulating agent targeting the reactive oxygen species which are important in the pathogenesis of disorders of mitochondrial oxidative phosphorylation. After demonstrating a favourable safety profile in the pre-clinical testing, the safety, tolerability and pharmacokinetic and pharmacodynamic characteristics of the compound will now be evaluated in healthy male subjects in this trial

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: Male

Target Recruitment: 32

Inclusion Criteria

Healthy as assessed by medical history, physical examination, Vital Signs, Clinical Laboratory, ECG

Exclusion Criteria

Allergies,
Concomitant medication,
concomitant disease,
relevant surgery,
recent blood donation

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Multiple Escalating	placebo	3 multiple escalating groups, receiving active/placebo
Single Escalating	placebo	2 alternating groups receiving escalating single doses of active/placebo
Multiple Escalating	KH176	3 multiple escalating groups, receiving active/placebo
Single Escalating	KH176	2 alternating groups receiving escalating single doses of active/placebo

Primary Outcome Measures

Name	Time	Method
SAD: Change From Baseline in ECG Results by Timepoint: Corrected QT Interval According to Fridericia's Formula (QTcF)	Baseline, 1, 2, 4, 6, 8, 12, 24 hours, 7 day follow up	The baseline ECG recording consists of a triplicate recording (3 recordings of a least 3 complexes within a 5 minute window) prior to dosing on Day 1. For the evaluation of the corrected QT intervals the average of the 3 recordings will be taken as baseline. Other ECG recordings will be singlet (one recording of at least 3 complexes) prior to dosing. QTcF is calculated as the quotient between the QT interval in milliseconds and the cube root of the RR interval in seconds, according to Fridericia's formula.
Change From Baseline in Hematology Laboratory Test Results by Timepoint: Hematocrit SAD Group	Baseline (pre-dose Day 1), 24 h postdose, FU (7 days after last dosing)	Hematocrit is a measure of the ratio of red blood cells (RBCs) in the blood by volume. Blood samples were collected from participants at the indicated timepoints for evaluation of hematology parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Hematology Laboratory Test Results by Timepoint: Mean Corpuscular Hemoglobin Concentration - SAD	Baseline (pre-dose Day 1), 24 h post dose, FU (7 days after last dosing)	Erythrocyte mean corpuscular hemoglobin concentration (MCHC) is a measure of the average concentration of hemoglobin per red blood cell. Blood samples were collected from participants at the indicated timepoints for evaluation of hematology parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Hematology Laboratory Test Results by Timepoint: Hemoglobin. MAD Group	Baseline (pre-dose Day 1), Day 3, Day 8, FU (7 days post dose)	Blood samples were collected from participants at the indicated timepoints for evaluation of hematology parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Hematology Laboratory Test Results by Timepoint: Mean Corpuscular Hemoglobin. MAD Group	Baseline (pre-dose Day 1), Day 3, Day 8, FU (7 days post dose)	Blood samples were collected from participants at the indicated timepoints for evaluation of hematology parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Pharmacodynamics of KH176	Day 1, day 7	Change from baseline in biochemistry related to Oxidative Phosphorylation (OXPHOS) (glutathione, lactate); MAD group
Change From Baseline in Hematology Laboratory Test Results by Timepoint: Erythrocyte Sedimentation Rate (SAD Group)	Baseline (pre-dose Day1), 24h post dose, FU (7 days after last dosing)
Change From Baseline in Hematology Laboratory Test Results by Timepoint: White Blood Cell Count. SAD Group	Baseline (pre-dose Day 1), 24h post dose, FU (7 days after last dosing)	Blood samples were collected from participants at the indicated timepoints for evaluation of hematology parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Hematology Laboratory Test Results by Timepoint: Lymphocytes. SAD Group	Baseline (pre-dose Day 1), 24h post dose, FU (7 days post dose)	Blood samples were collected from participants at the indicated timepoints for evaluation of hematology parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Hematology Laboratory Test Results by Timepoint: Red Blood Cell Count. SAD Group	Baseline (pre-dose Day 1), 24h post dose, FU (7 days after last dosing)	Blood samples were collected from participants at the indicated timepoints for evaluation of hematology parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Hematology Laboratory Test Results by Timepoint: Erythrocyte Sedimentation Rate MAD Group	Baseline (pre-dose Day 1), Day 3, Day 8, FU (7 days after last dosing)
Change From Baseline in Hematology Laboratory Test Results by Timepoint: Mean Corpuscular Volume - SAD	Baseline (pre-dose Day 1), 24 h post dose, FU (7 days after last dosing)	Blood samples were collected from participants at the indicated timepoints for evaluation of hematology parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
MAD: Change From Baseline in ECG Results by Time Point: QTcF	Baseline, Day1, Day 2, Day 3, Day 4, Day 5, Day 6, Day 7	The baseline ECG recording consists of a triplicate recording (3 recordings of a least 3 complexes within a 5 minute window) prior to dosing on Day 1. For the evaluation of the corrected QT intervals the average of the 3 recordings will be taken as baseline. Other ECG recordings will be singlet (one recording of at least 3 complexes) prior to dosing, or around the expected Cmax on Day 1 or 7 for the multiple-dose part. QTcF is calculated as the quotient between the QT interval in milliseconds and the cube root of the RR interval in seconds, according to Fridericia's formula.
Change From Baseline in Hematology Laboratory Test Results by Timepoint: Lymphocytes. MAD Group	Baseline (pre-dose Day 1), Day 3, Day 8, FU (7 days post dose)	Blood samples were collected from participants at the indicated timepoints for evaluation of hematology parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Relationship to Study Drug and Severity of Treatment-emergent Adverse Events	4 months
Change From Baseline in Hematology Laboratory Test Results by Timepoint: Thrombocytes. SAD Group	Baseline (pre-dose Day 1), 24h, FU (7 days post-dose)	Blood samples were collected from participants at the indicated timepoints for evaluation of hematology parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Hematology Laboratory Test Results by Timepoint: Basophils. SAD Group	Baseline (pre-dose Day 1), 24h post dose, FU (7 days post-dose)	Blood samples were collected from participants at the indicated timepoints for evaluation of hematology parameters. The baseline value at visit and the change from baseline value ateach timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Hematology Laboratory Test Results by Timepoint: Monocytes. SAD Group	Baseline (pre-dose Day 1), 24h post dose, FU (7 days post-dose)	Blood samples were collected from participants at the indicated timepoints for evaluation of hematology parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Hematology Laboratory Test Results by Timepoint: Red Blood Cell Count. MAD Group	Baseline (pre-dose Day 1), Day 3, Day 8, FU (7 days post dose)	Blood samples were collected from participants at the indicated timepoints for evaluation of hematology parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Hematology Laboratory Test Results by Timepoint: Eosinophils. MAD Group	Baseline (pre-dose Day 1), Day 3, Day 8, FU (7 days post dose)	Blood samples were collected from participants at the indicated timepoints for evaluation of hematology parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Hematology Laboratory Test Results by Timepoint: Thrombocytes. MAD Group	Baseline (pre-dose Day 1), Day 3, Day 8, FU (7 days post dose)	Blood samples were collected from participants at the indicated timepoints for evaluation of hematology parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Hematology Laboratory Test Results by Timepoint: Neutrophils. SAD Group	Baseline (pre-dose Day 1), 24h post dose, FU (7 days after last dosing)	Blood samples were collected from participants at the indicated timepoints for evaluation of hematology parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Hematology Laboratory Test Results by Timepoint: Mean Corpuscular Haemoglobin. SAD	Baseline (pre-dose Day 1), 24 h post dose, FU (7 days after last dosing)	Blood samples were collected from participants at the indicated timepoints for evaluation of hematology parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Hematology Laboratory Test Results by Timepoint: Hematocrit MAD Group	Baseline (pre-dose Day 1), Day 3, Day 8, FU (7 days post dose)	Hematocrit is a measure of the ratio of red blood cells (RBCs) in the blood by volume. Blood samples were collected from participants at the indicated timepoints for evaluation of hematology parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value
Change From Baseline in Hematology Laboratory Test Results by Timepoint: Eosinophils. SAD Group	Baseline (pre-dose Day 1), 24h post dose, FU (7 days after last dosing)	Blood samples were collected from participants at the indicated timepoints for evaluation of hematology parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Hematology Laboratory Test Results by Timepoint: Monocytes. MAD Group	Baseline (pre-dose Day 1), Day 3, Day 8, FU (7 days post dose)	Blood samples were collected from participants at the indicated timepoints for evaluation of hematology parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Total Protein. SAD Group	Baseline (pre-dose Day 1), 24h post dose, FU (7 days post dose)	Blood samples were collected from participants at the indicated timepoints for evaluation of clinical chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Hematology Laboratory Test Results by Timepoint: Mean Corpuscular Volume. MAD Group	Baseline (pre-dose Day 1), Day 3, Day 8, FU (7 days post dose)	Blood samples were collected from participants at the indicated timepoints for evaluation of hematology parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Hematology Laboratory Test Results by Timepoint: White Blood Cell Count. MAD	Baseline (pre-dose Day 1), Day 3, Day 8, FU (7 days post dose)	Blood samples were collected from participants at the indicated time points for evaluation of hematology parameters. The baseline value at visit and the change from baseline value at each time point are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Hematology Laboratory Test Results by Timepoint: Neutrophils. MAD Group	Baseline (pre-dose Day 1), Day 3, Day 8, FU (7 days post dose)	Blood samples were collected from participants at the indicated timepoints for evaluation of hematology parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Hematology Laboratory Test Results by Timepoint: Mean Corpuscular Haemoglobin Concentration. MAD Group	Baseline (pre-dose Day 1), Day 3, Day 8, FU (7 days post dose)	Blood samples were collected from participants at the indicated timepoints for evaluation of hematology parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Aspartate Aminotransferase. SAD Group	Baseline (pre-dose Day 1), 24h post dose, FU (7 days post dose)	Blood samples were collected from participants at the indicated timepoints for evaluation of clinical chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Chloride. SAD Group	Baseline (pre-dose Day 1), 24h post dose, FU (7 days post dose)	Blood samples were collected from participants at the indicated timepoints for evaluation of clinical chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Phosphate. SAD Group	Baseline (pre-dose Day 1), 24h post dose, FU (7 days post dose)	Blood samples were collected from participants at the indicated timepoints for evaluation of clinical chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Uric Acid. SAD Group	Baseline (pre-dose Day 1), 24h post dose, FU (7 days post dose)	Blood samples were collected from participants at the indicated timepoints for evaluation of clinical chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Chemistry Laboratory Test Results by Timepoint: (Fasting) Glucose. SAD Group	Baseline (pre-dose Day 1), 24h post dose, FU (7 days post dose)	Blood samples were collected from participants at the indicated timepoints for evaluation of clinical chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Human Serum Albumin. SAD Group	Baseline (pre-dose Day 1), 24h post dose, FU (7 days post dose)	Blood samples were collected from participants at the indicated timepoints for evaluation of clinical chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Chemistry Laboratory Test Results by Time Point: Sodium. MAD Group	Baseline, Day 3, Day 8, FU (one week after last dosing)	Blood samples were collected from participants at the indicated timepoints for evaluation of chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Hematology Laboratory Test Results by Timepoint: Basophils. MAD Group	Baseline (pre-dose Day 1), Day 3, Day 8, FU (7 days post dose)	Blood samples were collected from participants at the indicated timepoints for evaluation of hematology parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Creatinine. SAD Group	Baseline (pre-dose Day 1), 24h post dose, FU (7 days post dose)	Blood samples were collected from participants at the indicated timepoints for evaluation of clinical chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Potassium. SAD Group	Baseline (pre-dose Day 1), 24h post dose, FU (7 days post dose)	Blood samples were collected from participants at the indicated timepoints for evaluation of clinical chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Triglycerides. SAD Group	Baseline (pre-dose Day 1), 24h post dose, FU (7 days post dose)	Blood samples were collected from participants at the indicated timepoints for evaluation of clinical chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Thyroid-stimulating Hormone. SAD Group	Baseline (pre-dose Day 1), 24h post dose, FU (7 days post dose)	Blood samples were collected from participants at the indicated timepoints for evaluation of clinical chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Chemistry Laboratory Test Results by Time Point: Total Protein. MAD Group	Baseline (pre-dose Day1), Day 3, Day 8, FU (one week after last dosing)	Blood samples were collected from participants at the indicated timepoints for evaluation of hematology parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Chemistry Laboratory Test Results by Time Point: Total Bilirubin. MAD Group	Baseline, Day 3, Day 8, FU (one week after last dosing)	Blood samples were collected from participants at the indicated timepoints for evaluation of chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Chemistry Laboratory Test Results by Time Point: Urea. MAD Group	Baseline, Day 3, Day 8, FU (one week after last dosing)	Blood samples were collected from participants at the indicated timepoints for evaluation of chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Chemistry Laboratory Test Results by Time Point: Potassium. MAD Group	Baseline, Day 3, Day 8, FU (one week after last dosing)	Blood samples were collected from participants at the indicated timepoints for evaluation of chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Chemistry Laboratory Test Results by Time Point: Chloride. MAD Group	Baseline, Day 3, Day 8, FU (one week after last dosing)	Blood samples were collected from participants at the indicated timepoints for evaluation of chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Gamma-GT. SAD Group	Baseline (pre-dose Day 1), 24h post dose, FU (7 days post dose)	Blood samples were collected from participants at the indicated timepoints for evaluation of hematology parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value
Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Creatinine Kinase. SAD Group	Baseline (pre-dose Day 1), 24h post dose, FU (7 days post dose)	Blood samples were collected from participants at the indicated timepoints for evaluation of clinical chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Sodium. SAD Group	Baseline (pre-dose Day 1), 24h post dose, FU (7 days post dose)	Blood samples were collected from participants at the indicated timepoints for evaluation of clinical chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Lactate. SAD Group	Baseline (pre-dose Day 1), 24h post dose, FU (7 days post dose)	Blood samples were collected from participants at the indicated timepoints for evaluation of clinical chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Chemistry Laboratory Test Results by Time Point: Creatine Kinase. MAD Group	Baseline, Day 3, Day 8, FU (one week after last dosing)	Blood samples were collected from participants at the indicated timepoints for evaluation of chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Chemistry Laboratory Test Results by Time Point: Phosphate. MAD Group	Baseline, Day 3, Day 8, FU (one week after last dosing)	Blood samples were collected from participants at the indicated timepoints for evaluation of chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Alkaline Phosphatase. SAD Group	Baseline (pre-dose Day 1), 24h post dose, FU (7 days post dose)	Blood samples were collected from participants at the indicated timepoints for evaluation of clinical chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Total Bilirubin. SAD Group	Baseline (pre-dose Day 1), 24h post dose, FU (7 days post dose)	Blood samples were collected from participants at the indicated timepoints for evaluation of hematology parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Alanine Aminotransferase. SAD Group	Baseline (pre-dose Day 1), 24h post dose, FU (7 days post dose)	Blood samples were collected from participants at the indicated timepoints for evaluation of clinical chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Urea. SAD Group	Baseline (pre-dose Day 1), 24h post dose, FU (7 days post dose)	Blood samples were collected from participants at the indicated timepoints for evaluation of clinical chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Calcium (Corrected for Albumin). SAD Group	Baseline (pre-dose Day 1), 24h post dose, FU (7 days post dose)	Blood samples were collected from participants at the indicated timepoints for evaluation of clinical chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Lipase. SAD Group	Baseline (pre-dose Day 1), 24h post dose, FU (7 days post dose)	Blood samples were collected from participants at the indicated timepoints for evaluation of clinical chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Low Density Lipoproteins. SAD Group	Baseline (pre-dose Day 1), 24h post dose, FU (7 days post dose)	Blood samples were collected from participants at the indicated timepoints for evaluation of clinical chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Bicarbonate. SAD Group	Baseline (pre-dose Day 1), 24h post dose, FU (7 days post dose)	Blood samples were collected from participants at the indicated timepoints for evaluation of clinical chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Chemistry Laboratory Test Results by Time Point: Alkaline Phosphatase. MAD Group	Baseline, Day 3, Day 8, FU (one week after last dosing)	Blood samples were collected from participants at the indicated timepoints for evaluation of chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Chemistry Laboratory Test Results by Time Point: Aspartate Aminotransferase. MAD Group	Baseline, Day 3, Day 8, FU (one week after last dosing)	Blood samples were collected from participants at the indicated timepoints for evaluation of chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Chemistry Laboratory Test Results by Time Point: Gamma GT. MAD Group	Baseline, Day 3, Day 8, FU (one week after last dosing)	Blood samples were collected from participants at the indicated timepoints for evaluation of chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Chemistry Laboratory Test Results by Time Point: Creatinine. MAD Group	Baseline, Day 3, Day 8, FU (one week after last dosing)	Blood samples were collected from participants at the indicated timepoints for evaluation of chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Triiodothyronine (T3). SAD Group	Baseline (pre-dose Day 1), 24h post dose, FU (7 days post dose)	Blood samples were collected from participants at the indicated timepoints for evaluation of clinical chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Cholesterol. SAD Group	Baseline (pre-dose Day 1), 24h post dose, FU (7 days post dose)	Blood samples were collected from participants at the indicated timepoints for evaluation of clinical chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Thyroxine (T4). SAD Group	Baseline (pre-dose Day 1), 24h post dose, FU (7 days post dose)	Blood samples were collected from participants at the indicated timepoints for evaluation of clinical chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Chemistry Laboratory Test Results by Time Point: Lipase. MAD Group	Baseline, Day 3, Day 8, FU (one week after last dosing)	Blood samples were collected from participants at the indicated timepoints for evaluation of chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Chemistry Laboratory Test Results by Time Point: Lactate. MAD Group	Baseline, Day 3, Day 8, FU (one week after last dosing)	Blood samples were collected from participants at the indicated timepoints for evaluation of chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Phospholipidosis	Day 1, Day 7	Change from Day 1 to Day 7 in di-docosahexaenoyl (22:6)-bis(monoacylglycerol) phosphate (di-22:6-BMP) and normalized di-22:6-BMP (urine) - MAD
MAD: Change From Baseline in ECG Results by Time Point: Corrected QT Interval According to Barret's Formaula (QTcB)	Baseline (pre-dose Day 1), Day1, Day 2, Day 3, Day 4, Day 5, Day 6, Day 7, Follow-up	The baseline ECG recording consists of a triplicate recording (3 recordings of a least 3 complexes within a 5 minute window) prior to dosing on Day 1. For the evaluation the average of the 3 recordings will be taken as baseline. Other ECG recordings will be singlet (one recording of at least 3 complexes) prior to dosing, or around the expected Cmax on Day 1 or 7 for the multiple- dose part.
Terminal Elimination Half-life (T1/2) of KH176 Over 24 Hours: SAD	Pre-dose (5 min before dosing) and 0.5, 1, 1.5, 2, 3, 6, 8, 12, and 24 hours post-dose	Plasma concentrations of KH176 were analysed after single dose administration of doses 10mg, 30mg, 100mg (with and without food), 300mg, 800mg, 2000mg b.i.d.
Time to Maximum Concentration (Tmax) of KH176 Over 24 Hours: SAD	Pre-dose (5 min before dosing) and 0.5, 1, 1.5, 2, 3, 6, 8, 12, and 24 hours post-dose	Plasma concentrations of KH176 were analysed after single dose administration of doses 10mg, 30mg, 100mg (with and without food), 300mg, 800mg, 2000mg b.i.d.
Change From Baseline in Chemistry Laboratory Test Results by Time Point: Calcium (Corrected for Albumin). MAD Group	Baseline, Day 3, Day 8, FU (one week after last dosing)	Blood samples were collected from participants at the indicated timepoints for evaluation of chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Chemistry Laboratory Test Results by Timepoint: High Density Lipoproteins. SAD Group	Baseline (pre-dose Day 1), 24h post dose, FU (7 days post dose)	Blood samples were collected from participants at the indicated timepoints for evaluation of clinical chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Chemistry Laboratory Test Results by Time Point: Alanine Aminotransferase. MAD Group	Baseline, Day 3, Day 8, FU (one week after last dosing)	Blood samples were collected from participants at the indicated timepoints for evaluation of chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Chemistry Laboratory Test Results by Time Point: Thyroid-stimulating Hormone. MAD Group	Baseline, Day 3, Day 8, FU (one week after last dosing)	Blood samples were collected from participants at the indicated timepoints for evaluation of chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
MAD: Change From Baseline in ECG Results by Time Point: the Interval That Denotes Depolarization of the Ventricles, Between the Beginning of the Q Wave and the End of the S Wave (QRS Interval)	Baseline (pre-dose Day 1), Day1, Day 2, Day 3, Day 4, Day 5, Day 6, Day 7, Follow-up	The baseline ECG recording consists of a triplicate recording (3 recordings of a least 3 complexes within a 5 minute window) prior to dosing on Day 1. For the evaluation the average of the 3 recordings will be taken as baseline. Other ECG recordings will be singlet (one recording of at least 3 complexes) prior to dosing, or around the expected Cmax on Day 1 or 7 for the multiple- dose part.
SAD: Change From Baseline in ECG Results by Time Point: QRS Interval	Pre-dose, Day 1, Day 7	The baseline ECG recording consists of a triplicate recording (3 recordings of a least 3 complexes within a 5 minute window) prior to dosing on Day 1. For the evaluation the average of the 3 recordings will be taken as baseline.
SAD: Change From Baseline in ECG Results by Time Point: QTcB Interval	Pre-dose, Day1, Day 7	The baseline ECG recording consists of a triplicate recording (3 recordings of a least 3 complexes within a 5 minute window) prior to dosing on Day 1. For the evaluation the average of the 3 recordings will be taken as baseline.
Maximum Concentration (Cmax) of KH176: SAD Group	Pre-dose (5 min before dosing) and 0.5, 1, 1.5, 2, 3, 6, 8, 12, and 24 hours post-dose	Plasma concentrations of KH176 were analysed after single dose administration of doses 10mg, 30mg, 100mg (with and without food), 300mg, 800mg, 2000mg b.i.d.
Maximum Concentration (Cmax) of KH183 (Active Metabolite of KH176): MAD Group	Predose at Day 1, 2, 4, 7, and post-dose at Day 1 and Day 7 at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours	Plasma concentrations of KH183 were analysed after multiple-dose administration of doses of 100, 200 and 400 mg b.i.d.: Cmax was obtained directly from the concentration-time data.
Maximum Concentration (Cmax) of KH176: MAD	pre-dose at Day 1, 2, 4, 7, and post-dose at Day 1 and Day 7 at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours	Plasma concentrations of KH176 were analysed after multiple-dose administration of doses of 100, 200 and 400 mg b.i.d.
Time to Maximum Concentration (Tmax) of KH176 at Day 1, Day 7: MAD Group	pre-dose at Day 1, 2, 4, 7, and post-dose at Day 1 and Day 7 at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours	Plasma concentrations of KH176 were analysed after multiple-dose administration of doses of 100, 200 and 400 mg b.i.d.
Area Under the Plasma Concentration Versus Time Curve (AUClast) of KH183: SAD Group	Pre-dose (5 min before dosing) and 0.5, 1, 1.5, 2, 3, 6, 8, 12, and 24 hours post-dose	Plasma concentrations of KH183 were analysed after single dose administration of doses 10mg, 30mg, 100mg (with and without food) , 300mg, 800mg, 2000mg b.i.d.
Change From Baseline in Chemistry Laboratory Test Results by Time Point: Uric Acid. MAD Group	Baseline, Day 3, Day 8, FU (one week after last dosing)	Blood samples were collected from participants at the indicated timepoints for evaluation of chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Chemistry Laboratory Test Results by Time Point: High Density Lipoproteins. MAD Group	Baseline, Day 3, Day 8, FU (one week after last dosing)	Blood samples were collected from participants at the indicated timepoints for evaluation of chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Chemistry Laboratory Test Results by Time Point: Thyroxine (T4). MAD Group	Baseline, Day 3, Day 8, FU (one week after last dosing)	Blood samples were collected from participants at the indicated timepoints for evaluation of chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
SAD: Change From Baseline in ECG Results by Time Point: PQ Interval	Pre-dose, Day 1, Day 7	The baseline ECG recording consists of a triplicate recording (3 recordings of a least 3 complexes within a 5 minute window) prior to dosing on Day 1. For the evaluation the average of the 3 recordings will be taken as baseline.
Terminal Elimination Half-life (T1/2) of KH183: SAD	Pre-dose (5 min before dosing) and 0.5, 1, 1.5, 2, 3, 6, 8, 12, and 24 hours post-dose	Plasma concentrations of KH183 were analysed after single dose administration of doses 10mg, 30mg, 100mg (with and without food) , 300mg, 800mg, 2000mg b.i.d.
Maximum Concentration (Cmax) of KH183 Over 24 Hours: SAD	Pre-dose (5 min before dosing) and 0.5, 1, 1.5, 2, 3, 6, 8, 12, and 24 hours post-dose	Plasma concentrations of KH183 were analysed after single dose administration of doses 10mg, 30mg, 100mg (with and without food) , 300mg, 800mg, 2000mg b.i.d.
Area Under the Plasma Concentration Versus Time Curve (AUClast) of KH176: SAD Group	pre-dose (5 min before dosing) and 0.5, 1, 1.5, 2, 3, 6, 8, 12, and 24 hours post-dose	Plasma concentrations of KH176 were analysed after single dose administration of doses 10mg, 30mg, 100mg (with and without food), 300mg, 800mg, 2000mg b.i.d.
KH183: Percentage of Administered Dose Excreted in Urine: SAD	24 hours post-dose	Urine concentrations of KH176 were analysed after single dose administration of doses 10mg, 30mg, 100mg (with and without food), 300mg, 800mg, 2000mg b.i.d.
KH183: Percentage of Administered Dose Excreted in Urine: MAD	Post dose Day 7	Urine concentrations of KH183 were analysed after multiple-dose administration of doses of 100, 200 and 400 mg b.i.d.
KH173 + KH183: Percentage of Administered Dose Excreted in Urine: MAD	Day 7 Post dose	Urine concentrations of KH176 and KH183 were analysed after multiple-dose administration of doses of 100, 200 and 400 mg b.i.d.
Change From Baseline in Chemistry Laboratory Test Results by Time Point: Human Serum Albumin. MAD Group	Baseline, Day 3, Day 8, FU (one week after last dosing)	Blood samples were collected from participants at the indicated timepoints for evaluation of chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Chemistry Laboratory Test Results by Time Point: Fasting Glucose. MAD Group	Baseline, Day 3, Day 8, FU (one week after last dosing)	Blood samples were collected from participants at the indicated timepoints for evaluation of chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Chemistry Laboratory Test Results by Time Point: Trilodothyronine (T3). MAD Group	Baseline, Day 3, Day 8, FU (one week after last dosing)	Blood samples were collected from participants at the indicated timepoints for evaluation of chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
MAD: Change From Baseline in ECG Results by Time Point: P Wave-Q Wave Interval (PQ Interval)	Baseline (pre-dose Day 1), Day1, Day 2, Day 3, Day 4, Day 5, Day 6, Day 7, Follow-up	The baseline ECG recording consists of a triplicate recording (3 recordings of a least 3 complexes within a 5 minute window) prior to dosing on Day 1. For the evaluation of the PQ interval the average of the 3 recordings will be taken as baseline.
MAD: Change From Baseline in ECG Results by Time Point: QT Interval	Baseline (pre-dose Day 1), Day1, Day 2, Day 3, Day 4, Day 5, Day 6, Day 7, Follow-up	The baseline ECG recording consists of a triplicate recording (3 recordings of a least 3 complexes within a 5 minute window) prior to dosing on Day 1. For the evaluation the average of the 3 recordings will be taken as baseline. Other ECG recordings will be singlet (one recording of at least 3 complexes) prior to dosing, or around the expected Cmax on Day 1 or 7 for the multiple- dose part.
Time to Maximum Concentration (Tmax) of KH183 (Active Metabolite of KH176): MAD Group	Predose at Day 1, 2, 4, 7, and post-dose at Day 1 and Day 7 at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours	Plasma concentrations of KH183 were analysed after multiple-dose administration of doses of 100, 200 and 400 mg b.i.d.. tmax was obtained directly from the concentration-time data.
Accumulation Factor (Racc) of KH183 (Active Metabolite of KH176): MAD Group	Predose at Day 1, 2, 4, 7, and post-dose at Day 1 and Day 7 at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours	Plasma concentrations of KH183 were analysed after multiple-dose administration of doses of 100, 200 and 400 mg b.i.d.: Accumulation factor was calculated as follows: AUCtau day 7/ AUCtau day 1.
Area Under the Plasma Concentration-time Curve From Time Zero Until Infinity (AUCl0-inf) of KH183: SAD	Pre-dose (5 min before dosing) and 0.5, 1, 1.5, 2, 3, 6, 8, 12, and 24 hours post-dose	Plasma concentrations of KH183 were analysed after single dose administration of doses 10mg, 30mg, 100mg (with and without food) , 300mg, 800mg, 2000mg b.i.d.
KH176: Percentage of Administered Dose Excreted in Urine: SAD	24 hours post-dose	Urine concentrations of KH176 were analysed after single dose administration of doses 10mg, 30mg, 100mg (with and without food), 300mg, 800mg, 2000mg b.i.d.
KH176 + KH183: Percentage of Administered Dose Excreted in Urine: SAD	24 hours post-dose	Urine concentrations of KH176 were analysed after single dose administration of doses 10mg, 30mg, 100mg (with and without food), 300mg, 800mg, 2000mg b.i.d.
Change From Baseline in Chemistry Laboratory Test Results by Time Point: Cholesterol. MAD Group	Baseline, Day 3, Day 8, FU (one week after last dosing)	Blood samples were collected from participants at the indicated timepoints for evaluation of chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Chemistry Laboratory Test Results by Time Point: Triglycerides. MAD Group	Baseline, Day 3, Day 8, FU (one week after last dosing)	Blood samples were collected from participants at the indicated timepoints for evaluation of chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Chemistry Laboratory Test Results by Time Point: Low Density Lipoproteins. MAD Group	Baseline, Day 3, Day 8, FU (one week after last dosing)	Blood samples were collected from participants at the indicated timepoints for evaluation of chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
Change From Baseline in Chemistry Laboratory Test Results by Time Point: Bicarbonate. MAD Group	Baseline, Day 3, Day 8, FU (one week after last dosing)	Blood samples were collected from participants at the indicated timepoints for evaluation of chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
SAD: Change From Baseline in ECG Results by Time Point: QT Interval	Pre-dose, Day 1, Day 7	The baseline ECG recording consists of a triplicate recording (3 recordings of a least 3 complexes within a 5 minute window) prior to dosing on Day 1. For the evaluation the average of the 3 recordings will be taken as baseline.
Accumulation Factor (Racc) of KH176 Over 7 Days: MAD Group	Pre-dose at Day 1, 2, 4, 7, and post-dose at Day 1 and Day 7 at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours	Plasma concentrations of KH176 were analysed after multiple-dose administration of doses of 100, 200 and 400 mg b.i.d.. Racc was calculated as follows: AUCtau day 7/ AUCtau day 1.
Area Under the Plasma Concentration-time Curve (AUCtau) of KH176: MAD Group:	Pre-dose at Day 1, 2, 4, 7, and post-dose at Day 1 and Day 7 at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours	Plasma concentrations of KH176 were analysed after multiple-dose administration of doses of 100, 200 and 400 mg b.i.d.
Area Under the Plasma Concentration-time Curve During a Dose Interval (AUCtau) of KH183 (Active Metabolite of KH176): MAD Group	Predose at Day 1, 2, 4, 7, and post-dose at Day 1 and Day 7 at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours	Plasma concentrations of KH183 were analysed after multiple-dose administration of doses of 100, 200 and 400 mg b.i.d.
Area Under the Plasma Concentration-time Curve From Time Zero Until Infinity (AUCl0-inf) of KH176: SAD	Pre-dose (5 min before dosing) and 0.5, 1, 1.5, 2, 3, 6, 8, 12, and 24 hours post-dose	Plasma concentrations of KH176 were analysed after single dose administration of doses 10mg, 30mg, 100mg (with and without food) , 300mg, 800mg, 2000mg b.i.d.
KH176: Percentage of Administered Dose Excreted in Urine: MAD	Day 7 post dose	Urine concentrations of KH176 were analysed after multiple-dose administration of doses of 100, 200 and 400 mg b.i.d.
Time to Reach Peak Plasma Concentration (Tmax) of KH183: SAD	Pre-dose (5 min before dosing) and 0.5, 1, 1.5, 2, 3, 6, 8, 12, and 24 hours post-dose	Plasma concentrations of KH183 were analysed after single dose administration of doses 10mg, 30mg, 100mg (with and without food), 300mg, 800mg, 2000mg b.i.d.