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.
Trial Snapshot
- Phase
- Phase 2
- Status
- Completed
- Sponsor
- Khondrion BV
- Enrollment
- 27
- Locations
- 4
- Primary Endpoint
- Cognitive functioning: Attention
Study Overview
Brief Summary
Mitochondrial diseases, estimated prevalence 1 in 4,300 adults, is caused by pathogenic mutations in genes finally encoding for mitochondrial proteins of the various enzyme complexes of the OXPHOS. Among these mutations, the 3243A>G nucleotide change in the mitochondrially encoded transfer RNALeu(UUR) leucine 1 gene (MT TL 1) is the most prevalent one. The OXPHOS dysfunction resulting from such mutations leads to increased production of reactive oxygen species (ROS), ultimately leading to irreversible oxidative damage of macromolecules, or to more selective and reversible redox modulation of cell signaling that may impact (adult) neurogenesis.
Despite advances in the understanding of mitochondrial disorders, treatment options are extremely limited and, to date, largely supportive. Therefore, there is an urgent need for novel treatments. KH176, a new active pharmaceutical ingredient (API), is an orally bio-available small molecule under development for the treatment of these disorders (see Section 1.4). The current study will further evaluate the effect of KH176 in various cognitive domains and evaluate the effect of different doses of KH176 (See Section 1.5).
In view of the growing recognition of the importance of mitochondrial function in maintaining cognitive processes in the brain, as well as the understanding of the safety profile and pharmacokinetics of KH176 following the two clinical studies described above, a more detailed study is indicated of the effects of KH176 in various cognitive domains, using the confirmed safe and well-tolerated KH176 dose of 100 mg bid, as well as a lower dose of 50 mg bid. The primary objective is an evaluation of KH176 in the attention domain of cognitive functioning, as assessed by the visual identification test score of the Cogstate computerised cognitive testing battery.
Detailed Description
For this study, a 3 x 3 crossover design will be applied, i.e., with 3 treatments, 3 sequences and 3 periods, employing a Latin square assignment. Using this design, each subject will function as his/her own control. This will reduce variability and thus increase the chances of observing true effects between treatment periods (effects of treatment compared to placebo). In each treatment period, assessments will be performed at baseline prior to dosing and post dosing, enabling a change from baseline analysis and enabling the possibility to compare baseline conditions for each treatment period. The treatment period in each treatment is 28 days (4 weeks), which is supported by the pre-clinical toxicology program. In mouse studies, a 4-week period was sufficient to observe clinically relevant effects.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Crossover
- Primary Purpose
- Treatment
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- Not provided
Exclusion Criteria
- Not provided
Arms & Interventions
Treatment C
Oral administration of matching placebo twice daily
Intervention: Placebo (Drug)
Treatment A
Oral administration of 50 mg KH176 twice daily
Intervention: KH176 (Drug)
Treatment B
Oral administration of 100 mg KH176 twice daily
Intervention: KH176 (Drug)
Outcomes
Primary Outcomes
Cognitive functioning: Attention
Time Frame: One month
The attention domain score of cognitive functioning, as assessed by the visual Identification Test of the Cogstate computerised cognitive testing battery
Secondary Outcomes
- Executive functioning(One month)
- Psychomotor function(One month)
- Visual learning(One month)
- Verbal learning(One month)
- Number of headache days(One month)
- Pure Tone Audiometry (PTA)(One month)
- Working Memeory(One month)
- Beck Depression Inventory(One month)
- Cognitive Failure Questionnaire (CFQ)(One month)
- Newcastle Mitochondrial Disease Scale for Adults (NMDAS)(One month)
- University of Penn Smell Identification Test (UPSIT)(One month)
- Test of Attentional Performance (TAP)(One month)
- Hamilton Anxiety and Depression Score (HADS)(One month)
- Neuro-QoL Fatigue Short Form (quality in life in neurological disorders)(One month)