Mini-MARVEL study, children and young people with an active flare of UC requiring either the start of or an increase in existing mesalazine therapy will be given either MitoQ or placebo as a daily capsule for 24 weeks in the Mini-MARVEL M arm of the study. Those children and young people with an active flare of UC requiring the start of an oral steroid course will be given either MitoQ or placebo as a daily capsule for 24 weeks in the Mini- MARVEL S arm of the study, Further, newly diagnosed children and young people with UC can have either MitoQ or placebo as a daily capsule for 24 weeks with their newly started mesalazine therapy in the Mini-MARVEL M arm of the study, or with their newly started oral steroid course in the Mini-MARVEL S arm of the study. This trial will look at how feasible a multi-centre stratified RCT of this add-on (adjunct) therapy in paediatric UC is in the UK. An assessment after 6, 12 and 24 weeks will be carried out to find out if MitoQ will result in higher rates of improvement in the participants' symptoms, quality of life and gut lining inflammation. Furthermore, the trial will investigate if their UC will be better controlled and that they are less likely to need further steroids or more potent forms of drugs. MitoQ has been shown to be safe in 2 large human clinical studies in Parkinson's disease and Hepatitis C, but the Mini-MARVEL study, starting alongside the adult MARVEL study, will be the first study in UC in children and young people. At low doses, MitoQ is used as a nutritional supplement that has an anti-oxidant effect. Currently, many drug treatments in UC are very strong, expensive and aimed at suppressing the immune system. Steroid courses are often needed but these have lots of adverse events in children and young people and are strongly disliked by many. If the Mini- MARVEL study provides supportive data on feasibility, including where we have to concentrate our efforts to include enough children and young people through to study end, we could design a full-scale trial to see if MitoQ can be a safe and cost-effective new treatment that works at blocking the specific inflammatory signal found in the gut lining of children and young people with UC.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
OTHER
Masking
QUADRUPLE
MitoQ in inflammation: In the experimental setting, MitoQ has been extensively studied with clear mode of action on inflammatory mechanisms relevant to IBD: MitoQ can limit the damage to mitochondria caused by mitochondrial ROS and thereby reducing the leak and oxidisation of mtDNA that are critical to its pro-inflammatory actions within the cell. MitoQ reduces the inflammatory potential of mitochondrial DNA which have escaped or released from dying inflammatory cells. MitoQ can influence how the immune cells generate their energy, diverting it away from a more inflammatory type of metabolism (glycolysis) MitoQ can induce autophagy, a cellular recycling mechanism that removes damaged mitochondria. Defective autophagy is heavily implicated in the pathogenesis of IBD. Hence collectively, MitoQ acts upstream of several pro-inflammatory mechanisms with the net effect to promote resolution of inflammation and mucosal healing.
Placebo
NHS Lothian
Edinburgh, United Kingdom
Feasibility
Feasibility of a multi-centre placebo-controlled RCT of an add-on therapy in paediatric UC by the rate of participants recruited per centre over the 15 month recruitment period. Further feasibility parameters such as retention, , adherence and compliance, plus trial and drug acceptability will be assessed. Secondary outcome measures include clinical response and remission at Weeks 6 and 12; and remission, response, reductions in faecal calprotectin and steroid burden, quality of life, safety and tolerance) will be determined at Week 24.
Time frame: 24 weeks
Clincial Response
At Weeks 6, 12 and 24 measured using the validated paediatric UC disease activity score 'PUCAI' (drop in PUCAI score \>20 points or drop of \<20 with absolute score \<10 points)
Time frame: 6, 12, 24 weeks
Clinical remission
At weeks 6, 12 and 24 (defined as a PUCAI score \<10 points.
Time frame: 6, 12, 24 weeks
Clinical response and remission
score of 2 or less + no subscore \>1) at weeks 6, 12 and 24 on partial Mayo score (9 point score)
Time frame: 6, 12, 24 weeks
Difference in mean PUCAI scores at weeks 6, 12 and 24 weeks
Time frame: 6, 12, 24 weeks
Steroid-free remission rate at weeks 12 and 24
Time frame: 12 and 24 weeks
Steroid-free remission rate at week 24
Time frame: 24 weeks
Anti-TNF-free remission rate at week 24
Time frame: 24 weeks
Rate of new start iv and/or oral steroid course by week 24
Time frame: 24 weeks
Rate of new start immunomodulator (thiopurine/calcineurin inhibitor) by week 24
Time frame: 24 weeks
Rate of new start of biological (anti-TNF, vedolizumab, ustekinumab) by week 24
Time frame: 24 weeks
Proportions of participants with primary treatment failure with 24 week study period requiring escalation in medical treatment as below:
1. (i) Mini-MARVEL M - treatment with oral or intravenous corticosteroids (ii) Mini-MARVEL S - Re-treatment with oral or intravenous corticosteroids 2. Biologics (anti-TNF, anti-α4β7, anti-IL23 and oral Jak-inhibitors) 3. Azathioprine or 6-mercaptopurine in participants who were not on a thiopurine at baseline 4. Oral or intravenous ciclosporin OR oral tacrolimus
Time frame: 24 weeks
Reduction of stool calprotectin of >50% compared to baseline or near normalization (<250ug/g) of faecal calprotectin at week 12 and 24
Time frame: 12 and 24 weeks
Mucosal healing with faecal calprotectin <100ug/g at week 12 and at week 24
Time frame: 12 and 24 weeks
Cumulative steroid dose baseline to week 24 (steroid burden)
Time frame: 4 weeks
Quality of life (QoL) - the scores and change from baseline in the validated paediatric IBD quality-of-life score IMPACT 3 at week 12 and week 24
Time frame: 12 and 24 weeks
PROM (TUMMY UC) - the scores and change from baseline in the validated TUMMY UC score at week 12 and week 24
Time frame: 12 and 24 weeks
Rate and durations of UC-related hospitalizations
Time frame: 24 weeks
Rate of colectomy for UC or UC-related complications
Time frame: 24 weeks
Incidence and severity of adverse events/reactions and serious adverse events/reactions
Time frame: 24 weeks
Drug concentration analyses and research into biomarkers (mitochondrial DNA and formylated peptides) at Baseline, Week 12 and Week 24, plus pharmacogenomics (via DNA sample at Baseline)
Time frame: 12 and 24 weeks
Precision of the between group effect size (d) - this will be measured by the 95% confidence intervals (CI) around d.
Time frame: 24 weeks
Achievement of clinically meaningful effect with add-on therapy - we will evaluate if we can gain an estimate of size of clinically meaningful effect between MitoQ and placebo as add-on therapy
Time frame: 24 weeks
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