Clinical trial NCT04351698: SMILES: Study of Montelukast in Sickle Cell Disease
Official title: Study of Montelukast In ChiLdrEn With Sickle Cell Disease (SMILES)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
PHASE3
Conditions: Anemia, Sickle Cell
Sleep-Disordered Breathing
Lead sponsor: Great Ormond Street Hospital for Children NHS Foundation Trust
Sponsor class: OTHER
Collaborators: name: Guy's and St Thomas' NHS Foundation Trust
name: University College London Hospitals
name: North Middlesex University Hospital
name: King's College Hospital NHS Trust
name: The Whittington Hospital NHS Trust
First posted: 2020-04-17
Enrollment: 200
Sex: ALL
Minimum age (years): 3
Maximum age (years): 8
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Sickle cell disease (SCD) is a genetic blood condition causing long term health problems including pain and brain problems which affect quality of life. These may be made worse if patients have low night-time oxygen levels when the upper airways close repeatedly during the night (obstructive sleep apnoea). This is associated with increased pain, poorer concentration and increased kidney problems. Montelukast, widely used in the treatment of Asthma, has been shown to improve symptoms of obstructive sleep apnoea in patients without sickle cell anaemia. Investigators think this treatment could be useful in patients with sickle cell disease too. Early intervention with Montelukast could help prevent deterioration in concentration and thinking skills.

The aim of this trial is to see whether young children with sickle cell disease randomised (randomise: the same as tossing a coin and not knowing whether it will come up heads or tails) to Montelukast treatment have better thinking skills compared with people randomised to placebo (tablet with no active medical ingredients - i.e. "sugar pill"). This means that the child could be on Montelukast treatment or he/she might be on placebo tablets.

Detailed description: This trial, funded by Action Medical Research, will involve 200 SCD patients recruited from haematology clinics and ENT (ear, nose and throat) surgery waiting lists or their local sleep laboratory at Evelina Children's hospital (Guy's \& St Thomas), University College London hospital, North Middlesex hospital and Whittington Hospitals. Patients are eligible if they are between 3 and \<8 years old w SCD, give informed consent, have any Sleep-Disordered Breathing, e.g. snoring, and/or any abnormality on overnight oximetry. After consenting, the PI/Coordinator will organise a simple app-based questionnaire and baseline testing of brain speed, with an optional brain scan, and randomisation to chewable Montelukast tablets or Placebo for 3 months after which the brain speed tests, questionnaires and MRI will be repeated.

Purpose and design:

This is designed as a phase 2/3 trial of Montelukast therapy to investigate whether this drug improves processing speed, which appears to underpin the difference in full scale IQ (intelligence quotient) United Kingdom.

between children with sickle cell disease and their siblings.

Recruitment:

Patients will be recruited from the paediatric and adult sickle clinics at the involved hospitals. These clinics are attended by over 2000 patients with sickle cell disease.

This is a paediatric trial in a group of children who mainly belong to an ethnic minority as it is this age group who are vulnerable to sleep-disordered breathing (90% of children with sickle cell disease in our previous study snored). The investigators have successfully run 4 previous randomised controlled trials and 2 longitudinal studies in this group of children. The proposal has been developed by a multidisciplinary team of researchers/scientists, many of whom have lengthy clinical experience in this area. This team includes two patient representatives. Processing speed has been measured until recently using the Coding and Symbol search Wechsler subtests but investigators found that there was a practice effect in both arms of our pilot trial of continuous positive airways pressure, which was not seen for Cancellation, another test of processing speed and attention. The NIH toolbox processing speed is a new iPad test which has extensive normal data down to the age of 3 years, but a team member who has used it has found a practice effect. Investigators are therefore including 2 primary endpoints: Cancellation and the NIH toolbox processing speed It is possible that investigators will not recruit 200 patients across the 4 London sites so:

1. Investigators have ensured that they will be adequately powered to detect an effect of Montelukast on adenoid: nasopharynx ratio on MRI if they recruit at least 3 willing to undergo MRI in each arm; this will allow exploration of the secondary brain MRI endpoints in addition to the primary endpoints.
2. Investigators will extend to additional UK sites
3. Investigators will apply for additional funds to extend the study outside the UK, e.g. by applying for $500,000 from the National Heart Lung and Blood Institutes (USA) to run the study in Cincinnati and New York.

Eligibility criteria: Inclusion Criteria:

* Aged between 3 and \<8 years
* Informed consent with assent in accordance with institutional policies and European guidelines; ICF (informed consent form) must be signed by patients/guardian
* HbSS 9homozygous SS disease) or HbSβ0 thalassaemia diagnosed by standard techniques (HPLC, IEF (Isoelectric focusing), MS (Mass spectrometry) or AlkE)
* History of Sleep-Disordered Breathing, (i.e. parent-reported any degree of snoring (CHSQ questionnaire) and/or any abnormality on overnight oximetry compared with published data in children of the same age (e.g. nadir SO2 (oxygen saturation) \<93%; mean SO2\<96%))
* Able to speak and understand English

Exclusion Criteria:

* Other neurodevelopmental disorders
* Patient already on Montelukast
* Patient has had side effects on or an adverse reaction to Montelukast in the past

Primary outcomes:
measure: Change in processing speed scores from baseline to 12 weeks for participants with sickle cell disease randomised to the control arm or the treatment arm.
timeFrame: 12 weeks
measure: Change in processing speed scores from baseline to 12 weeks for participants with sickle cell disease randomised to the control arm or the treatment arm.
timeFrame: 12 weeks
Secondary outcomes:
measure: Change in executive function (from NIH Toolbox® Cognition Battery) from baseline to 12 weeks for participants with sickle cell disease randomised to the control arm or the treatment arm.
timeFrame: 12 weeks
measure: Change in executive function (parent reported questionnaire) from baseline to 12 weeks for participants with sickle cell disease randomised to the control arm or the treatment arm.
timeFrame: 12 weeks
measure: Change in sleep and respiratory symptoms from baseline to 12 weeks for participants with sickle cell disease randomised to the control arm or the treatment arm.
timeFrame: 12 weeks
measure: Change in pain symptoms from baseline to 12 weeks for participants with sickle cell disease randomised to the control arm or the treatment arm.
timeFrame: 12 weeks
measure: Number of Participants With Treatment-Related Adverse Events from Montelukast
timeFrame: 12 weeks
measure: Change in Brain MRI from baseline to 12 weeks for participants with sickle cell disease randomised to the control arm or the treatment arm.
timeFrame: 12 weeks
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: Great Ormond Street Hospital NHS Foundation Trust
Study officials:
affiliation: University College, London
name: Fenella Kirkham, MA MB Bchir
role: PRINCIPAL_INVESTIGATOR
References:
citation: Hood AM, Stotesbury H, Kolbel M, DeHaan M, Downes M, Kawadler JM, Sahota S, Dimitriou D, Inusa B, Wilkey O, Pelidis M, Trompeter S, Leigh A, Younis J, Drasar E, Chakravorty S, Rees DC, Height S, Lawson S, Gavlak J, Gupta A, Ridout D, Clark CA, Kirkham FJ. Study of montelukast in children with sickle cell disease (SMILES): a study protocol for a randomised controlled trial. Trials. 2021 Oct 10;22(1):690. doi: 10.1186/s13063-021-05626-6.