An Exploratory, Multicenter, Randomized, double-blind, placebo-controlled study evaluating the effect and safety of pitolisant in children and adolescents with Autism Spectrum Disorders.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Bioprojet Pharma

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Psychiatry and Psychology [F] - Behavior and Behavior Mechanisms [F01], Psychiatry and Psychology [F] - Mental Disorders [F03], Diseases [C] - Nervous System Diseases [C10]

Trial duration

10 Oct 2023 → 4 Nov 2025

Decision date (initial)

2023-08-21

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Bioprojet Pharma

External identifiers

EU CT number

2023-503678-18-00

WHO UTN

U1111-1292-0416

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

The primary objective of this study is to evaluate at the end of treatment period the effect of pitolisant treatment on the ASD social communication and interaction deficit core symptom as assessed by the SRS-2 Total score

Secondary objectives 3

1. To evaluate at the end of treatment period the effect of pitolisant on: o Social communication and interaction deficit core symptom as assessed by the SRS-2 sub-domains, o Social communication and daily living skills as assessed by VABS III, o Quality of sleep as assessed by CSHQ, o Hyperactivity and attention as assessed by Conners 4 ADHD Index (Conners 4 AI), o Improvement of Clinical global impression as assessed by CGI-I,
2. To investigate the pharmacokinetics of pitolisant and metabolites as appropriate
3. To evaluate the safety and tolerability of 3 months of treatment with pitolisant (including adverse events (AEs), Adverse Events of Special Interest (AESI), suicidal risk as measured by the Columbia-Suicide Severity Scale (C-SSRS), vital signs, 12-lead ECG and routine safety laboratory tests).

Conditions and MedDRA coding

Autism spectrum disorders

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Participants (if possessing adequate understanding, in the investigator's opinion) and their parent(s)/legal guardian(s) are willing and able to give informed assent and consent for participation in the study.
2. Participant has a care provider who can reliably bring participant to clinic visits, provide trustworthy ratings, support participant with study compliance requirements, and interacts with the participant on a regular basis (e.g., spends at minimum 3 hours/ day and 4 x /week).
3. The participant agrees to follow the contraceptive requirements detailed in the protocol.
4. Male and female children and adolescents aged from 6 to 17 inclusive for the duration of study participation.
5. Participants have an Intelligence Quotient (IQ) ≥ 70 using Wechsler Intelligence Scale (WAIS-IV, WISC-IV or WISC-V) confirmed by historical data within the last 3 years or at screening (WAIS-IV or WISC-V). If total IQ score is unconclusive due to heterogenicity of sub-scores, participant should have at minimum both sub-scores for verbal comprehension and perceptual reasoning ≥ 70.
6. Social Responsiveness Scale Second Edition (SRS-2) total T-score ≥ 66 at screening and baseline.
7. All ongoing medications or interventions (except those listed as prohibited in “previous and concomitant medications/therapy” section) for ASD related symptoms must have been stable for at least 4 weeks prior to screening, and the participant/caregiver must be willing to maintain a stable regimen throughout the study.
8. Participants’ language, hearing and vision must be compatible with the study assessments as judged by the investigator.
9. Participants must have the ability to swallow the investigational medicinal product (IMP).
10. Participants have a diagnosis of autism spectrum disorders as per the DSM-5 criteria confirmed by ADOS-2 or ADI-R historical diagnosis within the last 3 years prior to screening or by ADI-R at screening.
11. Participants should benefit from appropriate health insurance system (for French participant only).

Exclusion criteria 18

1. Known hypersensitivity to the investigational medicinal product including active substance and excipients.
2. Pregnant or lactating woman
3. History or current diagnosis of major depressive episode or severe psychiatric disorders, e.g., schizophrenia, bipolar disorder, organic brain syndrome or psychosis, preventing the participant from completing the study assessments per investigator judgement.
4. Other active clinically significant illness, infection, active acid-related gastric disorders, neoplastic pathology within the last 3 years, or any abnormalities identified following a physical examination of the participant that, in the opinion of the investigator could interfere with the study conduct or counter-indicate the study treatments or place the participant at risk during the study or compromise his study participation.
5. Participants having a diagnosis other than ASD that dominates the clinical presentation (e.g., Attention-Deficit/Hyperactivity Disorder (ADHD), anxiety disorder, depressive disorder) per investigator judgement.
6. Participant with a severe obesity or severe anorexia at screening as calculated by a Body Mass Index (BMI) at or above the 97th percentile and at or below the 3rd percentile, respectively for the same age.
7. Participant with a history of suicidal behavior or suicidal ideation in the past 12 months, or a positive answer to questions 4 or 5 on the Columbia-Suicide-Severity Rating Scale (C-SSRS) at screening and/or baseline, and/or is a significant risk for suicidal behavior per investigator judgement.
8. Participants with cardiac disorders including clinically significant deviation from normal on 12-lead ECG that results as per investigator judgement in an active medical problem, or with a QTcF > 450ms at screening, where they are co-medicated or not with QT-prolonging medicinal products or medicinal products known to increase the risk of repolarization disorders.
9. Any participant presenting congenital galactosemia, glucose-galactose malabsorption or lactase deficiency due to the presence of lactose in the investigational medical product (IMP).
10. Participants with clinically relevant abnormal laboratory values suggesting an unknown disease and requiring further clinical investigation per investigator judgement.
11. Known or suspected history of alcohol or illicit drug (e.g., cannabis, amphetamines or opioids when not prescribed and used under medical supervision) or any history of cocaine abuse/dependence prior to screening according to investigator judgement.
12. Any positive test of abuse drugs at screening.
13. Prior (within the last 4 weeks prior to screening) or current therapy with strong CYP2D6 inhibitor drugs, strong CYP3A4 inducer drugs, CYP3A4 substrates having a narrow therapeutic margin, QT-prolonging medicinal products or medicinal products known to increase the risk of repolarization, antipsychotics medications, first-generation antihistamines (H1-antagonists) crossing the blood-brain barrier and tricyclic antidepressants as detailed in the “previous and concomitant medications/therapy” section.
14. Participants taking part in another interventional study and/or the use of any investigational therapy within the 30 days prior to screening.
15. Participant with a family relationship to a person involved in the study at the investigator’s site, at the Clinical Research Organisation (CRO) or at the Sponsor.
16. Participants with impaired renal function (stages 2 to 4 according to the international classification of chronic kidney disease, i.e. creatinine clearance between 15 and 89 ml/min according to the CKD-EPI formula).).
17. Participants with moderate hepatic impairment (Child Pugh B) or with any other hepatic significant abnormality in the physical examination or ALAT or ASAT ≥ 2x Upper Limit of Normal (ULN) for age at laboratory results.
18. History or current diagnosis of epilepsy or any seizure occurring after the age of 5.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Change from baseline of the Social Responsiveness Scale Second Edition (SRS-2) total score to the end of treatment period.

Secondary endpoints 21

1. Change from baseline to the end of treatment period of SRS-2 Social Awareness sub-domain score
2. Change from baseline to the end of treatment period of SRS-2 Social Cognition sub-domain score
3. Change from baseline to the end of treatment period of SRS-2 Social Communication sub-domain score,
4. Change from baseline to the end of treatment period of SRS-2 Social Motivation sub-domain score
5. Change from baseline to the end of treatment period of SRS-2 Restricted Interests and Repetitive Behavior sub-domain score
6. Change from baseline to the end of treatment period of Vineland Adaptive Behavior Scale III (VABS III) total score
7. Change from baseline to the end of treatment period of Vineland Adaptive Behavior Scale III (VABS III) Communication sub-domain score
8. Change from baseline to the end of treatment period of Vineland Adaptive Behavior Scale III (VABS III) Daily Living Skills sub-domain score
9. Change from baseline to the end of treatment period of Vineland Adaptive Behavior Scale III (VABS III) Socialization sub-domain score,
10. Change from baseline to the end of treatment period of Child’s Sleep Habits Questionnaire (CSHQ) total score
11. Change from baseline to the end of treatment period of Conners 4 ADHD Index (Conners 4 AI) total score
12. Clinical Global Impression – Improvement (CGI-I) score at week 12 of treatment
13. Pharmacokinetics endpoint: Trough serum level of pitolisant prior to last IMP intake after 12 weeks of treatment.
14. Incidence of treatment discontinuation due to adverse events (AEs) and adverse drug reactions (ADRs)
15. Incidence of serious AEs
16. Incidence and severity of AEs
17. Incidence of AEs of special interest (AESI)
18. Incidence of emergence or worsening of symptoms as measured by the Columbia-Suicide Severity Scale (C-SSRS)
19. Incidence of abnormal vital signs: pulse rate, systolic blood pressure, diastolic blood pressure
20. Incidence of clinically significant abnormalities on 12-lead ECG parameters
21. Incidence of clinically significant abnormalities on laboratory parameters

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Bioprojet Pharma

Sponsor organisation

Bioprojet Pharma

Address

9 Rue Rameau

City

Paris

Postcode

75002

Country

France

Scientific contact point

Organisation

Bioprojet Pharma

Contact name

Clinical Medical Director and Medical Monitor

Public contact point

Organisation

Bioprojet Pharma

Contact name

Clinical Medical Director and Medical Monitor

Third parties 13

Locations

4 EU/EEA countries · 23 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 100 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

21 submissions — initial application plus substantial / non-substantial modifications