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), MIDD (Maternally Inherited Diabetes and Deafness), Leigh's Disease and LHON (Leber's Hereditary Optic Neuropathy). The current Proof of Concept study aims to explore the effects of treatment with KH176 for 4 weeks on clinical signs and symptoms and biomarkers of mitochondrial disease and to evaluate the safety and pharmacokinetics of KH176 in patients with m.3242A\>G related mitochondrial disease.
The trial will be a double blind, randomized, placebo-controlled, single-centre, two-way cross-over trial. Twenty patients, with a confirmed mitochondrial DNA tRNALeu(UUR) m.3243A\>G mutation and with clinical signs of mitochondrial disease, will be randomized over 2 groups (active or placebo first). After a screening period and a training session, each group will have 2 dosing periods of 28 days, with a washout period of at least 28 days in between. On these occasions, patients will receive 100 mg KH176 twice daily (treatment A) or a matching placebo (treatment B) twice daily for 28 days. Clinical assessments will be performed once in a training session prior to baseline, at baseline and in week 4 post dosing during each treatment phase (A and B). Testing conditions and circumstances, with respect to timing of the assessments, hospitalization and meals, will be standardized for each assessement period. Furthermore, assessments of biomarkers for mitochondrial functioning, pharmacokinetics and specific safety assessments will be performed weekly.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
20
Radboud University Medical Center
Nijmegen, Netherlands
Movement disorders
Rater assessed change from baseline of motoric abnormalities and movement characteristics
Time frame: one month
NMDAS
Change from baseline of the Newcastle Mitochondrial Disease Activity Score
Time frame: one month
Spirometric parameters (FVC,FEV1, PEF)
Change from baseline in spirometric parameters
Time frame: one month
Spirometric parameters (MIP, MEP)
Change from baseline in spirometric parameters
Time frame: one month
Sit to Stand Test (30 seconds)
Change from baseline assessment of the maximum number of sit-standings in 30 seconds time
Time frame: one month
Handgrip Dynamometry
Change from baseline assessment of the maximum grip strenght
Time frame: one month
6-min chewing test
Change from baseline assessment in rate of mastication
Time frame: one month
6-min chewing test
Change from baseline assessment of pain and tiredness (VAS) during a 6-min chewing test
Time frame: one month
6-MWT
Change from baseline assessment of the Distance during a 6-min Walk Test
Time frame: one month
RAND-SF36 score
Change from baseline in the RAND-SF36
Time frame: one month
HAD and BDI
Change from baseline in the Hospital Anxiety and Depression Scale (HAD), supplemented with a Beck Depression Index (BDI)
Time frame: one month
BDI
Change from baseline in the Beck Depression Index (BDI)
Time frame: one month
CIS
Change from baseline in the Checklist Individual Strength
Time frame: one month
TAP
Change from baseline assessment of alertness and mental flexibility during a Test of Attentional Performance (TAP)
Time frame: one month
Goal Attainment Scale
Assessment of pre-defined goal attainment during each treatment period
Time frame: one month
Registration of Motor Activity and Sleeping pattern
During each treatment period a continuous registration of Motor Activity and Sleeping pattern by accelerometer, assessing sleep quality, quantity and overall motor activity
Time frame: one month
Vital Signs
Change from Baseline assessment of vital signs (heart rate, blood pressure)
Time frame: one month
ECG
Change from Baseline assessment of ECG-intervals
Time frame: one month
Clinical Laboratory
Change from Baseline assessment of Clinical Laboratory parameters
Time frame: one month
Pharmacokinetics of KH176 and metabolites
Attainment of steady state and total exposure (AUC) at steady state conditions
Time frame: one month
Pharmacokinetics of KH176 and metabolites
Attainment of steady state and maximal concentrations (Cmax) at steady state conditions
Time frame: one month
Glutathione
Change from baseline assessment of the ratio of oxidized/reduced glutathione in blood samples (GSH/GSSG)
Time frame: one month
Blood biomarker FGF21
Change from baseline assessment of FGF21
Time frame: one month
Blood biomarker GDF15
Change from baseline assessment of GDF15
Time frame: one month
Blood biomarker PRDX1
Change from baseline assessment of PRDX1
Time frame: one month
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