Phase 1 N=32 Randomized Double-blind Treatment

A Dose-escalating Clinical Trial With KH176

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

Bottom Line

View on ClinicalTrials.gov: NCT02544217 ↗

Enrolled (actual)

Serious AEs

0.0%

Results posted

Nov 2020

Primary outcome: Primary: SAD: Change From Baseline in ECG Results by Timepoint: Corrected QT Interval According to Fridericia's Formula (QTcF) — 386.2; 395.0; 385.8; 399.3 msec

Study Design & Population

Study type: Interventional
Phase: Phase 1
Interventions: KH176 (Drug); placebo (Drug)
Age: Adult · 18+ yrs
Sex: Male
Sponsor: Khondrion BV
Primary completion: Sep 2015

Outcome Measures

Outcome	Result	p-value
PRIMARY SAD: Change From Baseline in ECG Results by Timepoint: Corrected QT Interval According to Fridericia's Formula (QTcF)	386.2; 395.0; 385.8; 399.3; 390.3; 393.5	—
PRIMARY Pharmacodynamics of KH176	872; 2083; 2275; 1584; 919; 1923	—
PRIMARY Relationship to Study Drug and Severity of Treatment-emergent Adverse Events	5; 2; 2; 5; 7; 1	—
PRIMARY Change From Baseline in Hematology Laboratory Test Results by Timepoint: Red Blood Cell Count. SAD Group	4.947; 4.933; 4.793; 5.030; 4.953; 5.137	—
PRIMARY Change From Baseline in Hematology Laboratory Test Results by Timepoint: Erythrocyte Sedimentation Rate (SAD Group)	2.3; 2.8; 1.3; 1.8; 2.0; 3.0	—
PRIMARY Change From Baseline in Hematology Laboratory Test Results by Timepoint: Erythrocyte Sedimentation Rate MAD Group	4.0; 3.0; 2.0; 2.7; 2.0; 0.8	—
PRIMARY Change From Baseline in Hematology Laboratory Test Results by Timepoint: Hematocrit SAD Group	43.77; 43.13; 43.10; 44.38; 42.98; 44.35	—
PRIMARY Change From Baseline in Hematology Laboratory Test Results by Timepoint: Mean Corpuscular Haemoglobin. SAD	30.32; 29.70; 30.78; 30.38; 30.00; 29.63	—
PRIMARY Change From Baseline in Hematology Laboratory Test Results by Timepoint: Mean Corpuscular Hemoglobin Concentration - SAD	34.15; 33.98; 34.18; 34.38; 34.53; 34.33	—
PRIMARY Change From Baseline in Hematology Laboratory Test Results by Timepoint: Mean Corpuscular Volume - SAD	88.75; 87.52; 90.15; 88.35; 86.93; 86.42	—
PRIMARY MAD: Change From Baseline in ECG Results by Time Point: QTcF	397.3; 384.3; 388.5; 393.0; 0.5; 5.5	—
PRIMARY Change From Baseline in Hematology Laboratory Test Results by Timepoint: White Blood Cell Count. SAD Group	4.435; 4.773; 4.313; 4.863; 4.395; 4.475	—
PRIMARY Change From Baseline in Hematology Laboratory Test Results by Timepoint: Lymphocytes. SAD Group	1570.0; 1748.3; 1655.0; 1862.5; 1485.0; 1570.0	—
PRIMARY Change From Baseline in Hematology Laboratory Test Results by Timepoint: Neutrophils. SAD Group	2276.7; 2296.7; 2117.5; 2365.0; 2380.0; 2197.5	—
PRIMARY Change From Baseline in Hematology Laboratory Test Results by Timepoint: Hematocrit MAD Group	39.93; 43.40; 45.10; 43.30; 2.67; 1.17	—
PRIMARY Change From Baseline in Hematology Laboratory Test Results by Timepoint: Eosinophils. SAD Group	115.0; 191.7; 110.0; 137.5; 112.5; 200.0	—
PRIMARY Change From Baseline in Hematology Laboratory Test Results by Timepoint: Thrombocytes. SAD Group	209.5; 204.0; 193.0; 223.0; 215.8; 203.8	—
PRIMARY Change From Baseline in Hematology Laboratory Test Results by Timepoint: Basophils. SAD Group	23.3; 25.0; 15.0; 30.0; 15.0; 32.5	—
PRIMARY Change From Baseline in Hematology Laboratory Test Results by Timepoint: Monocytes. SAD Group	445.0; 496.7; 407.5; 455.0; 397.5; 467.5	—
PRIMARY Change From Baseline in Hematology Laboratory Test Results by Timepoint: Mean Corpuscular Volume. MAD Group	87.00; 89.32; 86.43; 89.02; -0.05; 0.52	—
PRIMARY Change From Baseline in Hematology Laboratory Test Results by Timepoint: Hemoglobin. MAD Group	13.68; 15.23; 15.68; 14.82; 1.05; 0.42	—
PRIMARY Change From Baseline in Hematology Laboratory Test Results by Timepoint: White Blood Cell Count. MAD	5.463; 4.753; 5.378; 4.583; -0.435; 0.480	—
PRIMARY Change From Baseline in Hematology Laboratory Test Results by Timepoint: Neutrophils. MAD Group	3077.5; 2602.5; 2935.0; 2483.3; -567.5; 350.0	—
PRIMARY Change From Baseline in Hematology Laboratory Test Results by Timepoint: Mean Corpuscular Haemoglobin Concentration. MAD Group	34.28; 35.05; 34.75; 34.23; 0.30; 0.05	—
PRIMARY Change From Baseline in Hematology Laboratory Test Results by Timepoint: Lymphocytes. MAD Group	1627.5; 1498.5; 1750.0; 1508.3; 87.5; 159.0	—
PRIMARY Change From Baseline in Hematology Laboratory Test Results by Timepoint: Mean Corpuscular Hemoglobin. MAD Group	29.80; 31.33; 30.03; 30.47; 0.25; 0.23	—
PRIMARY Change From Baseline in Hematology Laboratory Test Results by Timepoint: Red Blood Cell Count. MAD Group	4.588; 4.858; 5.217; 4.873; 0.313; 0.100	—
PRIMARY Change From Baseline in Hematology Laboratory Test Results by Timepoint: Eosinophils. MAD Group	212.5; 183.5; 127.5; 141.7; -40.0; -31.0	—
PRIMARY Change From Baseline in Hematology Laboratory Test Results by Timepoint: Monocytes. MAD Group	505.0; 424.0; 530.0; 418.3; 75.0; -11.5	—
PRIMARY Change From Baseline in Hematology Laboratory Test Results by Timepoint: Thrombocytes. MAD Group	207.3; 211.5; 199.8; 206.7; 15.5; 17.5	—
PRIMARY Change From Baseline in Hematology Laboratory Test Results by Timepoint: Basophils. MAD Group	30.0; 34.0; 20.0; 23.3; 7.5; 8.5	—
PRIMARY Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Aspartate Aminotransferase. SAD Group	20.5; 16.8; 19.3; 17.5; 18.3; 20.8	—
PRIMARY Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Total Protein. SAD Group	67.5; 65.5; 67.0; 67.3; 65.3; 66.0	—
PRIMARY Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Gamma-GT. SAD Group	23.5; 19.0; 24.0; 23.0; 12.0; 17.3	—
PRIMARY Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Alkaline Phosphatase. SAD Group	62.0; 64.0; 66.0; 75.0; 66.0; 68.3	—
PRIMARY Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Creatinine. SAD Group	0.927; 0.768; 0.903; 0.810; 0.838; 0.735	—
PRIMARY Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Chloride. SAD Group	102.7; 104.0; 103.8; 104.0; 102.3; 103.0	—
PRIMARY Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Total Bilirubin. SAD Group	0.82; 0.75; 1.03; 0.68; 1.18; 0.53	—
PRIMARY Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Alanine Aminotransferase. SAD Group	20.2; 17.2; 19.3; 20.0; 15.0; 19.3	—
PRIMARY Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Creatinine Kinase. SAD Group	118.2; 78.7; 181.8; 78.8; 209.3; 82.3	—
PRIMARY Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Urea. SAD Group	27.5; 24.7; 30.0; 26.0; 24.0; 25.3	—
PRIMARY Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Sodium. SAD Group	141.8; 142.5; 141.5; 142.8; 141.5; 142.0	—
PRIMARY Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Potassium. SAD Group	4.25; 4.27; 4.25; 4.18; 4.03; 4.33	—
PRIMARY Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Phosphate. SAD Group	1.042; 0.998; 1.120; 1.085; 1.023; 0.983	—
PRIMARY Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Calcium (Corrected for Albumin). SAD Group	2.380; 2.303; 2.290; 2.288; 2.373; 2.358	—
PRIMARY Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Uric Acid. SAD Group	5.52; 4.85; 5.75; 4.80; 5.48; 4.75	—
PRIMARY Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Triiodothyronine (T3). SAD Group	3.65; 3.23; 3.73; 3.40; 3.48; 3.18	—
PRIMARY Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Lipase. SAD Group	31.0; 34.8; 39.0; 29.3; 27.3; 33.0	—
PRIMARY Change From Baseline in Chemistry Laboratory Test Results by Timepoint: (Fasting) Glucose. SAD Group	85.0; 86.8; 84.8; 88.5; 77.8; 86.3	—
PRIMARY Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Human Serum Albumin. SAD Group	46.2; 45.0; 45.3; 45.0; 45.3; 46.0	—
PRIMARY Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Cholesterol. SAD Group	176.0; 151.0; 146.3; 149.0; 146.5; 167.5	—
PRIMARY Change From Baseline in Chemistry Laboratory Test Results by Timepoint: High Density Lipoproteins. SAD Group	50.0; 49.8; 45.5; 49.5; 40.0; 54.5	—
PRIMARY Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Triglycerides. SAD Group	72.8; 88.5; 57.3; 84.5; 72.0; 71.0	—
PRIMARY Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Low Density Lipoproteins. SAD Group	111.1; 83.5; 88.9; 82.5; 92.3; 98.7	—
PRIMARY Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Bicarbonate. SAD Group	25.68; 25.22; 24.78; 25.85; 24.85; 24.28	—
PRIMARY Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Thyroid-stimulating Hormone. SAD Group	1.45; 1.26; 1.14; 1.14; 1.50; 1.55	—
PRIMARY Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Thyroxine (T4). SAD Group	1.27; 1.22; 1.30; 1.38; 1.25; 1.08	—
PRIMARY Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Lactate. SAD Group	7.98; 7.28; 8.65; 8.23; 8.10; 9.03	—
PRIMARY Change From Baseline in Chemistry Laboratory Test Results by Time Point: Total Protein. MAD Group	65.3; 67.3; 63.8; 66.0; 4.0; 2.3	—
PRIMARY Change From Baseline in Chemistry Laboratory Test Results by Time Point: Alkaline Phosphatase. MAD Group	66.0; 67.3; 55.3; 52.3; 7.3; 2.0	—
PRIMARY Change From Baseline in Chemistry Laboratory Test Results by Time Point: Aspartate Aminotransferase. MAD Group	20.3; 21.5; 18.5; 23.0; -2.0; -5.0	—
PRIMARY Change From Baseline in Chemistry Laboratory Test Results by Time Point: Creatine Kinase. MAD Group	129.5; 192.3; 146.5; 229.8; -48.5; -68.8	—
PRIMARY Change From Baseline in Chemistry Laboratory Test Results by Time Point: Gamma GT. MAD Group	15.5; 18.3; 20.5; 21.5; 0.5; 0.3	—
PRIMARY Change From Baseline in Chemistry Laboratory Test Results by Time Point: Total Bilirubin. MAD Group	0.50; 0.55; 0.63; 0.65; 0.38; 0.05	—
PRIMARY Change From Baseline in Chemistry Laboratory Test Results by Time Point: Urea. MAD Group	24.8; 28.0; 29.8; 30.2; 6.0; 2.8	—
PRIMARY Change From Baseline in Chemistry Laboratory Test Results by Time Point: Creatinine. MAD Group	0.910; 0.960; 0.913; 0.897; 0.095; 0.122	—
PRIMARY Change From Baseline in Chemistry Laboratory Test Results by Time Point: Sodium. MAD Group	143.8; 141.3; 141.0; 142.0; -0.5; -1.5	—
PRIMARY Change From Baseline in Chemistry Laboratory Test Results by Time Point: Potassium. MAD Group	4.20; 4.35; 4.40; 4.32; 0.45; 0.33	—
PRIMARY Change From Baseline in Chemistry Laboratory Test Results by Time Point: Chloride. MAD Group	103.8; 101.5; 102.0; 102.2; -2.5; -2.0	—
PRIMARY Change From Baseline in Chemistry Laboratory Test Results by Time Point: Calcium (Corrected for Albumin). MAD Group	2.278; 2.310; 2.265; 2.323; 0.105; 0.083	—
PRIMARY Change From Baseline in Chemistry Laboratory Test Results by Time Point: Uric Acid. MAD Group	5.65; 4.93; 5.40; 5.25; 0.50; 0.58	—
PRIMARY Change From Baseline in Chemistry Laboratory Test Results by Time Point: Lipase. MAD Group	26.5; 26.5; 32.8; 34.2; -1.8; 0.0	—
PRIMARY Change From Baseline in Chemistry Laboratory Test Results by Time Point: Alanine Aminotransferase. MAD Group	25.3; 21.3; 20.5; 22.3; 0.0; -0.3	—
PRIMARY Change From Baseline in Chemistry Laboratory Test Results by Time Point: Phosphate. MAD Group	0.978; 1.033; 0.920; 1.000; 0.102; 0.003	—
PRIMARY Change From Baseline in Chemistry Laboratory Test Results by Time Point: Human Serum Albumin. MAD Group	43.3; 45.5; 42.8; 44.7; 3.3; 3.8	—
PRIMARY Change From Baseline in Chemistry Laboratory Test Results by Time Point: Fasting Glucose. MAD Group	89.0; 85.5; 89.8; 87.2; -6.8; 2.8	—
PRIMARY Change From Baseline in Chemistry Laboratory Test Results by Time Point: Cholesterol. MAD Group	192.8; 191.0; 203.5; 177.8; 20.0; 8.8	—
PRIMARY Change From Baseline in Chemistry Laboratory Test Results by Time Point: Triglycerides. MAD Group	140.3; 83.5; 114.0; 90.2; 14.8; 35.5	—
PRIMARY Change From Baseline in Chemistry Laboratory Test Results by Time Point: Low Density Lipoproteins. MAD Group	114.1; 112.9; 127.0; 93.3; 17.9; 4.9	—
PRIMARY Change From Baseline in Chemistry Laboratory Test Results by Time Point: High Density Lipoproteins. MAD Group	51.0; 61.0; 53.5; 66.8; -1.0; -3.0	—
PRIMARY Change From Baseline in Chemistry Laboratory Test Results by Time Point: Thyroid-stimulating Hormone. MAD Group	1.41; 1.48; 1.20; 1.58; 0.11; 0.09	—
PRIMARY Change From Baseline in Chemistry Laboratory Test Results by Time Point: Trilodothyronine (T3). MAD Group	3.35; 3.35; 3.30; 3.08; -0.05; -0.28	—
PRIMARY Change From Baseline in Chemistry Laboratory Test Results by Time Point: Thyroxine (T4). MAD Group	1.20; 1.25; 1.20; 1.07; 0.05; 0.02	—
PRIMARY Change From Baseline in Chemistry Laboratory Test Results by Time Point: Bicarbonate. MAD Group	27.53; 25.53; 28.53; 27.23; -0.38; 2.20	—
PRIMARY Change From Baseline in Chemistry Laboratory Test Results by Time Point: Lactate. MAD Group	8.63; 7.00; 7.23; 9.12; 0.98; 2.23	—
PRIMARY Phospholipidosis	-1.473; -3.465; -2.630; -1.592; 1.298; 0.060	—
PRIMARY MAD: Change From Baseline in ECG Results by Time Point: Corrected QT Interval According to Barret's Formaula (QTcB)	391.3; 381.0; 384.0; 385.2; 3.8; 12.3	—
PRIMARY MAD: Change From Baseline in ECG Results by Time Point: P Wave-Q Wave Interval (PQ Interval)	185.8; 160.5; 162.0; 171.8; 2.8; -1.5	—
PRIMARY 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)	99.3; 92.5; 85.5; 98.5; 1.3; 2.0	—
PRIMARY MAD: Change From Baseline in ECG Results by Time Point: QT Interval	410.5; 391.5; 399.0; 410.2; -5.5; -7.5	—
PRIMARY SAD: Change From Baseline in ECG Results by Time Point: PQ Interval	195.5; 165.0; 154.5; 159.8; 155.0; 176.5	—
PRIMARY SAD: Change From Baseline in ECG Results by Time Point: QRS Interval	103.0; 97.0; 99.3; 97.8; 106.5; 92.5	—
PRIMARY SAD: Change From Baseline in ECG Results by Time Point: QT Interval	400.0; 415.0; 393.3; 416.0; 404.0; 409.0	—
PRIMARY SAD: Change From Baseline in ECG Results by Time Point: QTcB Interval	379.3; 385.5; 382.0; 390.5; 383.8; 386.3	—
PRIMARY Terminal Elimination Half-life (T1/2) of KH176 Over 24 Hours: SAD	0; 10.3; 9.10; 9.64; 9.80; 11.5	—
PRIMARY Terminal Elimination Half-life (T1/2) of KH183: SAD	16.6; 17.8; 15.4; 14.3; 17.2; 18.9	—
PRIMARY Maximum Concentration (Cmax) of KH176: SAD Group	12.9; 56.2; 167; 766; 2170; 5990	—
PRIMARY Maximum Concentration (Cmax) of KH183 Over 24 Hours: SAD	14.2; 49.4; 168; 497; 1100; 1780	—
PRIMARY Maximum Concentration (Cmax) of KH183 (Active Metabolite of KH176): MAD Group	99.4; 251; 550; 152; 250; 450	—
PRIMARY Maximum Concentration (Cmax) of KH176: MAD	184; 313; 1330; 353; 748; 2100	—
PRIMARY Time to Maximum Concentration (Tmax) of KH176 Over 24 Hours: SAD	1.03; 1.03; 0.931; 1.10; 1.36; 0.931	—
PRIMARY Time to Reach Peak Plasma Concentration (Tmax) of KH183: SAD	1.32; 1.46; 1.32; 1.31; 1.61; 1.57	—
PRIMARY Time to Maximum Concentration (Tmax) of KH176 at Day 1, Day 7: MAD Group	1.57; 1.73; 0.866; 0.931; 1.86; 1.36	—
PRIMARY Time to Maximum Concentration (Tmax) of KH183 (Active Metabolite of KH176): MAD Group	2.06; 1.57; 1.22; 1.19; 1.46; 1.61	—
PRIMARY Accumulation Factor (Racc) of KH176 Over 7 Days: MAD Group	2.52; 2.65; 2.17	—
PRIMARY Accumulation Factor (Racc) of KH183 (Active Metabolite of KH176): MAD Group	1.86; 1.32; 1.19	—
PRIMARY Area Under the Plasma Concentration Versus Time Curve (AUClast) of KH183: SAD Group	151; 547; 1810; 4830; 11700; 23900	—
PRIMARY Area Under the Plasma Concentration Versus Time Curve (AUClast) of KH176: SAD Group	75; 389; 1310; 6320; 21000; 61200	—
PRIMARY Area Under the Plasma Concentration-time Curve (AUCtau) of KH176: MAD Group:	1090; 2250; 6890; 2760; 5960; 14900	—
PRIMARY Area Under the Plasma Concentration-time Curve During a Dose Interval (AUCtau) of KH183 (Active Metabolite of KH176): MAD Group	702; 1680; 3600; 1310; 2220; 4270	—
PRIMARY Area Under the Plasma Concentration-time Curve From Time Zero Until Infinity (AUCl0-inf) of KH183: SAD	234; 881; 2690; 6690; 18700; 41300	—
PRIMARY Area Under the Plasma Concentration-time Curve From Time Zero Until Infinity (AUCl0-inf) of KH176: SAD	0; 474; 1540; 7500; 25800; 79100	—
PRIMARY KH176: Percentage of Administered Dose Excreted in Urine: SAD	9.71; 10.5; 10.4; 9.53; 10.9; 12.4	—
PRIMARY KH183: Percentage of Administered Dose Excreted in Urine: SAD	4.56; 6.42; 5.18; 3.81; 3.86; 3.33	—
PRIMARY KH176 + KH183: Percentage of Administered Dose Excreted in Urine: SAD	14.4; 17.2; 15.8; 13.4; 14.8; 15.9	—
PRIMARY KH176: Percentage of Administered Dose Excreted in Urine: MAD	14.9; 13.4; 14.0	—
PRIMARY KH183: Percentage of Administered Dose Excreted in Urine: MAD	5.30; 3.79; 4.85	—
PRIMARY KH173 + KH183: Percentage of Administered Dose Excreted in Urine: MAD	20.7; 17.4; 19.0	—

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

Eligibility Criteria

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

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Data sourced from ClinicalTrials.gov (NCT02544217). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.