Clinical Trials Register

Summary
EudraCT Number:	2019-000599-40
Sponsor's Protocol Code Number:	KH176-202
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2019-09-05
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2019-000599-40

A.3

Full title of the trial

A Phase IIb double-blind, randomised, placebo-controlled, multi-centre, confirmative three-way cross-over study on cognitive function with two doses of KH176 in subjects with a genetically confirmed mitochondrial DNA tRNALeu(UUR) m.3243A>G mutation.

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A study to evaluate the efficacy of KH176 in patients with a genetically confirmed mitochondrial DNA mutation. Patients to be allocated randomly to placebo or investigational drug in different periods; meaning each patient will receive both placebo as well as the investigational drug. Assignment of actual treatment order will be unknown to patient and doctor.

A.3.2

Name or abbreviated title of the trial where available

KHENERGYZE

A.4.1

Sponsor's protocol code number

KH176-202

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Khondrion B.V.
B.1.3.4	Country	Netherlands
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Khondrion B.V.
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Julius Clinical
B.5.2	Functional name of contact point	Bas Nieuwenhuis
B.5.3	Address:
B.5.3.1	Street Address	Broederplein 41-43
B.5.3.2	Town/ city	Zeist
B.5.3.3	Post code	3703 CD
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	0031 30 6569129
B.5.6	E-mail	bas.nieuwenhuis@juliusclinical.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/14/1336
D.3 Description of the IMP
D.3.1	Product name	KH176
D.3.2	Product code	KH176
D.3.4	Pharmaceutical form	Powder for oral solution
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	KH176
D.3.9.3	Other descriptive name	KH176
D.3.9.4	EV Substance Code	AS1
D.3.10	Strength
D.3.10.1	Concentration unit	Bq/mg becquerel(s)/milligram
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	50 to 100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Oral solution
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

A genetically confirmed mitochondrial desoxyribonucleic acid (DNA) transfer ribonucleic acid (tRNA)Leu(UUR) m.3243A>G mutation (including but not limited to MELAS, MIDD and mixed compositions).

E.1.1.1

Medical condition in easily understood language

Mitochondrial disease

E.1.1.2

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the effect of KH176 during a 4 week treatment period on the attention domain score of cognitive functioning, as assessed by the visual identification test of the Cogstate computerised cognitive testing battery.

E.2.2

Secondary objectives of the trial

To evaluate the effect of KH176 during a 4-week treatment period on the cognitive domains:
1. executive functioning
2. working memory
3. psychomotor function
4. visual learning
5. verbal learning
To evaluate the effect of KH176 during a 4-week treatment period on:
1. TAP
2. BDI
3. HADS
4. NMDAS
5. number of headache days, intensity and duration, and use of medication to relieve headache
6. hearing
7. smell identification
8. Cognitive Failure Questionnaire (CFQ)
9. Neuro-QoL Fatigue Short Form
To evaluate the effect of KH176 during a 4-week treatment period on:
1. the tolerability and safety of two doses of KH176 following 28 days of oral administration
2. Electrocardiogram (ECG) intervals, rhythm and morphology
Other objectives:
1. To investigate the multiple dose pharmacokinetics of KH176 following 28 days of oral administration

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Males and females aged 18 years or older at screening.
2. Ability and willingness to provide written Informed Consent prior to screening evaluations.
3. Confirmed mitochondrial DNA tRNALeu(UUR) m.3243A>G mutation (heteroplasmy ≥ 20%, urinary epithelial cells).
4. Positive NMDAS score >10 at Screening.
5. Three or more clinical features, with no other causative unifying diagnosis, found to commonly occur in subjects with a m.3243A>G mutation:
- Deafness
- Developmental delay
- Diabetes Mellitus
- Epilepsy
- Gastrointestinal complaints
- Progressive External Ophtalmoplegia (PEO) and retinopathy
- Ataxia
- Exercise intolerance
- Fatigue
- Migraine (with or without aura), specified by at least five attacks fulfilling diagnostic criteria B-D:
B. Headache attacks lasting 4-72 hours (untreated or unsuccessfully treated)
C. Headache has at least two of the following four characteristics:
1. unilateral location
2. pulsating quality
3. moderate or severe pain intensity
4. aggravation or causing avoidance of routine physical activity (e.g. walking or climbing stairs)
D. During headache at least one of the following:
1. nausea and/or vomiting
2. photophobia and phonophobia
6. Attentional dysfunction score (Cogstate Identification test) ≥ 0.2 standard deviations poorer than healthy controls at Screening.
7. Disease appropriate physical and mental health as established at Screening by medical history, physical examination, ECG and vital signs recording, and results of clinical chemistry and haematology testing as judged by the investigator.
8. Objectified Left Ventricular Ejection Fraction (LVEF) ≥45% (echocardiography, or otherwise).
9. Left Ventricular (LV) wall thickness ≤15 mm.
10. Left atrium dilatation ≤ 40 mL/m2.
Note: No need to test LV parameters (criteria #7, #8, #9) if favorable echocardiography (or otherwise) results dated less than 6 months prior to Screening are available.
11. Women of childbearing potential must be willing to use adequate contraceptive methods during the entire study, i.e., a hormonal contraceptive method (pill, vaginal ring, patch, implant, injectable, hormone-medicated intrauterine device) or an intrauterine device. Sexual abstinence is an acceptable contraceptive method only as true abstinence: when this is in line with the preferred and usual lifestyle of the patient. [Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception].
Note 1: Natural family planning methods, female condom, cervical cap or diaphragm are not considered adequate contraceptive methods in the context of this study.
Note 2: To be considered not of childbearing potential, potential female subjects must be post-menopausal for at least two years, or have been surgically sterilised (bilateral tubal ligation, hysterectomy or bilateral oophorectomy) for at least 6 months prior to Screening.
Note 3: KH176 has been shown non-genotoxic judged from the Ames test, Chromosomal Aberration test and in vivo Micronucleus test. Moreover, appreciable systemic exposure from the exposure to (~2.5 mL) semen is extremely unlikely. However, until reproductive toxicology studies have confirmed that KH176 does not adversely affect normal reproduction in adult males and females, as well as causing developmental toxicity in the offspring, male subjects with female partners of childbearing potential must be willing to use condoms during the entire study.
12. Able to comply with the study requirements, including swallowing study medication.

E.4

Principal exclusion criteria

1. Surgery of gastro-intestinal tract that might interfere with absorption.
2. Participation in a study of an investigational product in the preceding 3 months prior to the first dose or during this study.
3. Documented history of ventricular tachycardia (HR>110 beats/min).
4. (Family) history of acute heart failure, unexplained syncope of congenital long QT syndrome.
5. Clinically relevant abnormal laboratory, vital signs or physical or mental health at Screening or Baseline as judged by the investigator.
6. Clinically relevant abnormal ECG or cardiac functioning, defined as ST-segment elevation > 1 mm in I, II, III, aVL ,aVF ,V3 ,V4 ,V5 ,V6; > 2 mm in V1, V2; QTc > 450 ms (local, machine read), T-top inversion in >1 consecutive lead.
7. Serum Hyper-potassium (> 5.0 mEq/L).
8. Serum Hypo-potassium (< 3.5 mEq/L).
9. History of ischemic heart disease.
10. Symptomatic heart failure.
11. Clinically relevant aorta and/or mitralis valvular defect as judged by the investigator.
12. Pregnancy or breast feeding (females).
13. Poor nutritional state as judged by the investigator.
14. History of hypersensitivity or idiosyncrasy to any of the components of the investigational drug.
15. Within 4 weeks prior to dosing, the use of:
a. (multi)vitamins, co-enzyme Q10, Vitamine E, riboflavin, and anti-oxidant supplements (including, but not limited to idebenone/EPI-743, mitoQ); unless stable for at least one month before first dosing and remaining stable throughout the study.
b. any medication negatively influencing mitochondrial functioning (including but not limited to valproic acid, glitazones, statins, anti-virals, amiodarone, and non-steroidal anti-inflammatory drugs (NSAIDs)), unless stable for at least one month before first dosing and remaining stable throughout the study.
Note: thus, mitoQ and any medication negatively influencing mitochondrial functioning are allowed as long as the dose has been stable for at least one month prior to first dosing and remains stable throughout the study.
c. any strong Cytochrome P450 (CYP)3A4 inhibitors (all ‘conazoles-anti-fungals’, HIV antivirals, grapefruit).
d. strong CYP3A4 inducers (including HIV antivirals, carbamazepine, phenobarbital, phenytoin, rifampicine, St Johns wort, pioglitazone, troglitazone).
e. any medication known to affect cardiac repolarisation (all anti-psychotics, several anti-depressants: nor/amytriptilline, fluoxetine, anti-emetics: domperidone (motilium) granisetron, ondansetron).
f. any medication metabolised by CYP with a narrow therapeutical width.

E.5 End points

E.5.1

Primary end point(s)

Changes from baseline (measured at pre-dose Day 1) to end of treatment (Day 28 of each treatment period) in:
• the attention domain score of cognitive functioning, as assessed by the visual identification test of the Cogstate computerised cognitive testing battery.

E.5.1.1

Timepoint(s) of evaluation of this end point

For each treatment period: pre-dose day 1 (baseline) and day 28
Follow up (28 days after day 28 of last treatment period)

E.5.2

Secondary end point(s)

Changes from baseline (measured at pre-dose Day 1) to end of treatment (Day 28 of each treatment period) in the following domains of cognitive functioning:
• executive functioning
• working memory
• psychomotor function
• visual learning
• verbal learning
Changes from baseline (measured at pre-dose Day 1) to end of treatment (Day 28 of each treatment period) in:
• Test of Attentional Performance (TAP): Alertness and Mental Flexibility
• Hospital Anxiety and Depression Scale (HADS), supplemented with a Beck Depression Index (BDI)
• NMDAS Score
• number of headache days, intensity and duration and use of medication to relieve headache
• hearing (PTA)
• smell identification test (UPSIT)
• CFQ (overall score and 4 subscores)
• Neuro-QoL Fatigue Short Form

E.5.2.1

Timepoint(s) of evaluation of this end point

For each treatment period: pre-dose day 1 (baseline) and day 28
Follow up (28 days after day 28 of last treatment period)

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

Yes

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Other dosage of the same IMP

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1