A Phase 3 Efficacy and Safety Study of Pitolisant in Patients with Prader-Willi Syndrome

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Harmony Biosciences LLC

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16], Phenomena and Processes [G] - Genetic Phenomena [G05]

Trial duration

19 Mar 2025 → ongoing

Decision date (initial)

2025-02-11

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Harmony Biosciences

External identifiers

EU CT number

2023-508307-21-00

ClinicalTrials.gov

NCT06366464

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

Efficacy: To evaluate the impact of pitolisant on severity of EDS in patients with PWS

Secondary objectives 8

1. Efficacy: To evaluate the impact of pitolisant on severity of irritable and disruptive behaviors in patients with PWS
2. Efficacy: To evaluate the impact of pitolisant on overall severity of EDS in patients with PWS
3. Efficacy: To further evaluate the impact of pitolisant on overall severity of irritable and disruptive behaviors in patients with PWS
4. Efficacy: To evaluate the impact of pitolisant on severity of hyperphagia in patients with PWS
5. Efficacy: To further evaluate the impact of pitolisant on severity of EDS in patients with PWS
6. Efficacy: To evaluate the impact of pitolisant on severity of behavioral problems of PWS, including social withdrawal, stereotypic behavior, hyperactivity/noncompliance, and inappropriate speech
7. Safety and Pharmacokinetic: To evaluate the safety of pitolisant in patients with PWS
8. Safety and Pharmacokinetic: To evaluate the concentration of pitolisant in patients with PWS

Conditions and MedDRA coding

Prader-Willi syndrome

Study design 4 periods

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-001176-PIP01-11

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. 1. Male or female ages ≥6 years at the time of Screening.
2. 2. Ability to provide voluntary, written informed consent (parent[s]/caregiver[s]/legal guardian[s]) and, where applicable, voluntary, written assent (patient, as appropriate).
3. 3. A diagnosis of PWS confirmed by genetic testing and patient medical records. Genetic testing for PWS will be provided by the Sponsor if not confirmed based on the review of the patient’s medical records.
4. 4. & 5. Patient meets criteria for EDS per questionnaires
5. 6. Patient meets appropriate number of hours of sleep per night based on their age.
6. 7. If taking nonprohibited chronically administered concomitant medication or supplements, patient must be on a stable dose for at least 30 days prior to Screening and agree to remain on that stable dose during the Double-Blind Treatment Period or agree to washout of these medications or supplements for at least 5 half-lives prior to Screening.
7. 8. If taking hormone treatments (including growth hormone, testosterone, and estrogen supplements), patient must be on a stable dose of these medications for 30 days prior to Screening and during the Double-Blind Treatment Period; 20% variability in hormone dose is allowed.
8. 9. If using cannabidiol and/or tetrahydrocannabinol, patient must be on a stable dose for 30 days prior to Screening and agree to continue on that stable dose for the duration of the Double-Blind Treatment Period of the study or agree to washout of this treatment for at least 5 half-lives prior to Screening.
9. 10. If taking a strong CYP2D6 inhibitor, patient must be on a stable dose for at least 30 days prior to Screening and remain on that stable dose during the Double-Blind Treatment Period of the study or agree to washout of the medication for at least for 5 half-lives prior to Screening.
10. 11. Patients with a history of seizures must have a stable seizure history (e.g., frequency and severity) for at least 6 months prior to Screening.
11. 12. A patient who is an FCBP must have a negative serum pregnancy test at Screening and a negative urine pregnancy test at Baseline and agree to remain abstinent or use an effective method of nonhormonal contraception to prevent pregnancy for the duration of the study and for 21 days after final dose of study drug. Patients using hormonal contraception must also use an alternative nonhormonal contraceptive method during treatment with pitolisant and for at least 21 days after discontinuing treatment. An FCBP is defined as a female who is post-menarcheal, has an intact uterus and at least 1 ovary, and is <1 year postmenopausal. Male patients who are not azoospermic (vasectomized or due to a medical cause) must agree to use a barrier method of contraception for the duration of the study and for 21 days after the final dose of study drug.
12. 13. Has a consistent parent/caregiver (preferably the same person throughout the study) who is willing and able to complete the required study assessments.
13. 14. In the opinion of the Investigator, the patient/parent(s)/caregiver(s)/legal guardian(s) are capable of understanding and complying with the requirements of the protocol and administration of oral study drug.

Exclusion criteria 21

1. 1. Diagnosis of sleep apnea (OSA, CSA) that is not adequately controlled at the discretion of the Investigator.
2. 2. Has a diagnosis of hypersomnia due to another sleep/medical disorder.
3. 3. Has previously taken pitolisant.
4. 4. Participation in an interventional research study involving another investigational medication, device, or behavioral treatment within 30 days or within 5 half-lives (whichever is longer) of the investigational medication prior to Screening.
5. 5. Has a primary psychiatric diagnosis of ps5. Has a primary psychiatric diagnosis of psychosis or schizophrenia.ychosis or schizophrenia.
6. 6. Has a history of moderate hepatic impairment (Child-Pugh Class B) or severe hepatic impairment (Child-Pugh C).
7. 7. Has a history of eGFR <60 mL/min/1.73 m2.
8. 8. Has abnormal laboratory values at Screening that are clinically significant as determined by the Investigator.
9. 9. Has a known history of long QT syndrome or any significant history of a serious abnormality of the ECG (e.g., recent myocardial infarction, clinically significant arrhythmia).
10. 10. Has a QTcF with a mean value of >450 msec (QTcF=QT/3√ RR) at Screening based on the mean of triplicate 12-lead ECGs.
11. 11. Has a family history of sudden cardiac death, unexplained death, or death from a primary dysrhythmia potentially associated with QT prolongation in any family member.
12. 12. Has a current or recent (within 1 year) history of a substance use disorder or dependence disorder as defined in the DSM-V.
13. 13. Has surgery planned during the Double-Blind Treatment Period of the study.
14. 14. Is receiving a concomitant medication that is known to be a centrally acting H1R antagonist; patients who complete a washout for at least 5 half-lives prior to Screening are eligible.
15. 15. Is receiving a concomitant medication that is known to be a strong CYP3A4 inducer; patients who complete a washout for at least 5 half-lives prior to Screening are eligible.
16. 16. Is receiving a concomitant medication that is known to prolong the QT interval; patients who complete a washout for at least 5 half-lives prior to Screening are eligible.
17. 17. Has a significant risk of committing suicide based on history, routine psychiatric examination, Investigator’s judgment, or answering "yes" to question 4 or 5 on the C-SSRS at Screening or Baseline, or with any suicidal behavior within the last 12 months before Screening.
18. 18. Is currently breastfeeding or planning to breastfeed over the course of the study. Lactating women must agree not to breastfeed for the duration of the study and for 7 days after final dose of study drug.
19. 19. Has been deprived of liberty by administrative or judicial decision.
20. 20. Has a known hypersensitivity to the inactive ingredients of pitolisant or placebo tablets.
21. 21. Based on the judgment of the Investigator, is unsuitable for the study for any reason, including but not limited to unstable or uncontrolled medical conditions (including psychiatric and neurological conditions) or a medical condition that might interfere with the conduct of the study, confound interpretation of study results, pose a health risk to the patient, or compromise the integrity of the study.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Efficacy: Change in severity of EDS as measured by PROMIS SRI T-score from Baseline to the end of the Double Blind Treatment Period (Day 77)

Secondary endpoints 9

1. Efficacy: Change in severity of irritable and disruptive behaviors as measured by ABC-C Irritability Domain score from Baseline to the end of the Double-Blind Treatment Period (Day 77)
2. Efficacy: Change in overall severity of EDS as measured by the CaGI-S for EDS score from Baseline to the end of the Double-Blind Treatment Period (Day 77)
3. Efficacy: Change in overall severity of EDS as measured by the CGI-S for EDS score from Baseline to the end of the Double-Blind Treatment Period (Day 77)
4. Efficacy: Change in overall severity of irritable and disruptive behaviors as measured by the CaGI-S for Irritable and/or Disruptive Behaviors score from Baseline to the end of the Double-Blind Treatment Period (Day 77)
5. Efficacy: Change in severity of hyperphagia as measured by HQ CT score in conjunction with the FSZQ score, from Baseline to the end of the Double-Blind Treatment Period (Day 77)
6. Efficacy: Change in severity of EDS as measured by ESS CHAD (parent/caregiver version) total score from Baseline to the end of the Double-Blind Treatment Period (Day 77)
7. Efficacy: Change in severity of other behavioral problems as measured by the ABC-C Hyperactivity/Noncompliance, Inappropriate Speech, Social Withdrawal, and Stereotypic Behavior Domain scores from Baseline to the end of the Double-Blind Treatment Period (Day 77)
8. Safety and Pharmacokinetic: Percentage of patients reporting TEAEs during each study period and during the entire study
9. Safety and Pharmacokinetic: Measured concentration of pitolisant

Investigational products

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

Test 4

Placebo 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Harmony Biosciences LLC

Sponsor organisation

Harmony Biosciences LLC

Address

630 West Germantown Pike Suite 215

City

Plymouth Meeting

Postcode

19462-1069

Country

United States

Scientific contact point

Organisation

Harmony Biosciences LLC

Contact name

Regulatory Affairs Department

Public contact point

Organisation

Harmony Biosciences LLC

Contact name

Regulatory Affairs Department

Third parties 10

Locations

10 EU/EEA countries · 25 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

Documents 172 files

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

Application history

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