NIZUBAGLUSTAT for Niemann-Pick type C disease|GM1 gangliosidosis|GM2 gangliosidosis

Stratification factors

• Annual Severity Increment Score (ASIS) group (0.00 to 1; 1.01 to 1.75; >1.75)
• Concurrent use or non-use of approved treatments (arimoclomol and/or levacetylleucine)
• Disease type (GM1 or GM2 gangliosidosis)
• Age at study entry (<10 or ≥10 years)

Inclusion criteria

• {"criterion_text":"- 1. Provide written informed consent signed by the participant or their legal guardian, or parent. The parent and/or legal guardian can read, understand, and sign informed consent. Where appropriate, assent will also be sought for participants aged <18 years.\n- 6. Willing and able to complete assessments.\n- 7. Able to take study medication.\n- 8. Females of childbearing potential (defined as a premenopausal female capable of becoming pregnant) are eligible if: •\tsexually inactive and willing to stay inactive during the study (sexual abstinence for the 14 days prior to the first study drug dose and confirmation of continued abstinence until 28 days after the last dose) •\tusing one of the following highly-effective contraceptives (i.e. <1% failure rate when used consistently and correctly) for 14 days prior to the first study drug dose and continuing until 28 days after the last dose: intrauterine device; surgical sterilization of the partner (vasectomy for a minimum of 6 months); combined (estrogen or progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, or transdermal); progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, or implantable); or an intrauterine hormone release system.\n- 9. Females of non-childbearing potential •\twho have undergone one of the following sterilization operations at least 6 months prior to receiving the first dose of study drug: hysteroscopic sterilization, bilateral salpingectomy, hysterectomy, bilateral oophorectomy OR •\twho are postmenopausal with at least 1 year of amenorrhea and follicle stimulating hormone (FSH) serum values consistent with postmenopausal status. At Screening postmenopausal women will have their FSH levels analyzed and central laboratory FSH levels should fall within the postmenopausal range. \"•\tare pre-menarchal at Screening and agree to stay sexually inactive during the study and until 28 days after the last dose or are using one of the contraceptive methods listed in inclusion criterion 8.\n- 14. For subprotocol AZA-001-301-NPC only: Patient is unable or willing to take miglustat, or is, in the opinion of the investigator, unsatisfactorily treated with miglustat.\n- 10. Non-vasectomized male participants are eligible if they consent to use a spermicide-impregnated condom or abstain from sexual activity until 90 days after the last dose of study medication; their female partner is required to consent to comply with this inclusion criterion.\n- 11. A vasectomized male who had the procedure at least 6 months before starting the study is eligible if they consent to use a condom during sexual activity. A man vasectomized less than 6 months before commencement of the study must adhere to the same restrictions as a non-vasectomized male.\n- 12.\tMale participants agree not to donate sperm from the start of study treatment until 90 days after the final dose. Female participants agree not to donate eggs from the start of treatment of treatment until 90 days after the final dose (though this would not be permitted because of the nature of the underlying disease).\n- 13. The participant is willing to give information relating to current drugs/therapies used to manage symptoms of their conditions, including restricted medications.\n- 2a.\tConfirmed diagnosis of NPC disease based on: •The presence of biallelic pathogenic or likely pathogenic variants according to the American College of Medical Genetics and Genomics classification OR •One pathogenic or likely pathogenic variant and one variant of unknown significance, if clinical symptomatology is compatible with the disease and at least one disease biomarker (PPCS or C-triol) is over the normal laboratory range.\n- 3. Newly-diagnosed and/or treatment-naïve patients that are unwilling or unable to take NPC-approved treatments (eg. miglustat)\n- 4. Onset of neurological symptoms from 2 to 15 years.\n- 5. Disability level at Baseline: Ataxic disturbances with a total SARA score of ≥3 and <30 at Baseline: those with a total SARA score of ≥5 can enter the study automatically; inclusion of those with a total SARA score of 3 to 5 should be discussed with and approved by the Medical Monitor."}

Exclusion criteria

• {"criterion_text":"- 1.\tAny condition at Baseline that, in the opinion of the Principal Investigator, could interfere with study assessments (e.g., severe infection, severe cognitive impairment).\n- 13. ECG with an average QTcF interval of >450 msec for males and of >470 msec for females.\n- For subprotocol AZA-001-301-GMx only: 14. Received migulstat in the 12 months prior to Baseline, unless •the dose was lower than the maximum dose specified in the miglustat Summary of Product Characteristics for patients with NPC disease, OR •the total duration of miglustat dosing was less than 12 months. Any participants receiving miglustat are required to undergo a 1-month washout period before starting study medication.\"\n- 15. Known allergy to azasugars or any study drug excipient.\n- 16. Evidence of suicidal ideation with intent (Type 4 to 5) on the Columbia Suicide Severity Rating Scale (C-SSRS) at Screening; this requirement is only applicable to participants judged by the Principal Investigator to be cognitively capable of understanding the concept of suicide.\n- 2. A history of medical conditions other than NPC or GM1 or GM2 gangliosidosis that, in the opinion of the Principal Investigator, would confound scientific rigor or the interpretation of results.\n- 4. The presence of another neurologic disease.\n- 5. 5. The presence of moderate or severe hepatic impairment (alanine aminotransferase [ALT], aspartate aminotransferase [AST] and gamma-glutamyl transferase levels of >3x the upper limit of normal (ULN).\n- 12. A positive serum pregnancy test (for women of childbearing potential).\n- 6. The presence of moderate or severe renal impairment (estimated glomerular filtration rate of <30 ml/min/1.73m2).\n- 7.\tTotal bilirubin of >2x ULN isolated bilirubin of >2x ULN is acceptable if bilirubin is fractionated and direct bilirubin is <35%).\n- 8. Platelet count of <100x109/L.\n- 9.\tThe dose of any anti-epileptic treatment(s) was not stable (required a change in dose within the previous 3 months) and/or a new anti-epileptic treatment (drug or procedure) was prescribed in the month before Baseline.\n- 10. Prior use of an investigational drug within the 3 months prior to Screening, unless the product has since been approved and the participant is receiving a stable dose;\n- 3.Body weight of <10 kg.\n- For subprotocol AZA-001-301-NPC only: 14. Current treatment with miglustat, provided the patient •\thas been using the recommended dose as specified in the Summary of Product Characteristics for miglustat (see Appendix 4) for most of the past 12 months AND •\tis, in the opinion of the investigator, satisfactorily treated with miglustat. Any participants receiving miglustat are required to undergo a 1-month washout period before starting study medication.\n- 11. Prior participation in a clinical study involving gene therapy or stem cell transplantation within the 2 years prior to Screening"}

Primary endpoints

• {"endpoint_text":"- Change from Baseline to Week 72 in cale for Assessment and Rating of Ataxia (SARA) score, using both total SARA and functional SARA.","definition_or_measurement_approach":"Change from baseline to Week 72 measured by the Scale for Assessment and Rating of Ataxia (SARA), using total SARA and functional SARA scores."}

Secondary endpoints

• {"endpoint_text":"- 1. Change from Baseline to Weeks 24, 48, and 72 in: • SARAGAIT/POSTURE • SARASPEECH • SARAKINETICS • Vineland Adaptative Behavior Scale (VABS) comprehensive interview form • Penetration-Aspiration Scale (PAS)","definition_or_measurement_approach":"Change from baseline to Weeks 24, 48, 72 in specified SARA subdomains, VABS comprehensive interview form, and PAS as listed."}
• {"endpoint_text":"- 2. Change from Baseline to Weeks 24, 48, and 72 in: • 9-Hole Peg Test (9-HPT-D): change in the number of pegs per second placed in 50-seconds using the dominant hand • Goal attainment scale (GAS) • Clinical global impression of change (CGI-C) • Participant/caregiver global impression of change (PGI-C) • Seizure frequency and duration, as per the seizure diary","definition_or_measurement_approach":"Change from baseline at Weeks 24, 48, 72 measured by 9-HPT-D (pegs/sec), GAS, CGI-C, PGI-C, and seizure diary-recorded frequency/duration."}
• {"endpoint_text":"- Cont.Translation- Portuguese and French","definition_or_measurement_approach":"Continuation note referencing seizure frequency and duration per seizure diary (Portuguese/French translations)."}
• {"endpoint_text":"- 3. Time-to-event comparison between nizubaglustat and placebo over the study duration for pre-defined detrimental events of: •\tAn increase in total SARA score of ≥2 points and/or an increase in functional SARA of ≥1.5 points •\tA decrease in PAS of ≥1 point •\tParticipants leaving the study due to participant/caregiver perception of disease progression/lack of efficacy.","definition_or_measurement_approach":"Time-to-event analysis comparing arms for prespecified detrimental events (SARA increase ≥2 or functional SARA ≥1.5; PAS decrease ≥1; study withdrawal for perceived progression/lack of efficacy)."}
• {"endpoint_text":"- 4. For subprotocol AZA-001-301-NPC only, change from Baseline in NPC Clinical Severity Scale (NPC-CSS) score","definition_or_measurement_approach":"Change from baseline in NPC Clinical Severity Scale score (NPC-CSS) for NPC subprotocol participants."}
• {"endpoint_text":"- 5. The concentrations of nizubaglustat and its metabolites in plasma. The main PK parameters assessed will be: •Maximum observed plasma concentration (Cmax) and time to Cmax (Tmax) • Plasma trough concentration (Ctrough) at Week 4 • Area under the plasma concentration-time curve from the time of dosing (zero) to 24 hours post-dose (AUC0-24) at Baseline • Accumulation ratio for Cmax.","definition_or_measurement_approach":"Plasma PK sampling to determine Cmax, Tmax, Ctrough at Week 4, AUC0-24 at baseline, and accumulation ratio for Cmax."}
• {"endpoint_text":"- 6. Change from Baseline to Weeks 4, 24, 48 and 72 in the plasma GlcCer C16:0; C18:0 concentration.","definition_or_measurement_approach":"Change from baseline in plasma GlcCer C16:0 and C18:0 concentrations at Weeks 4, 24, 48, 72."}
• {"endpoint_text":"- 7. Change from Baseline to Weeks 24 and 48 comparing nizubaglustat and placebo in terms of: •Total and functional SARA score","definition_or_measurement_approach":"Between-arm comparison of change from baseline to Weeks 24 and 48 in total and functional SARA scores."}
• {"endpoint_text":"- 8. Change from Baseline to Weeks 24, 48 and 72 comparing nizubaglustat and placebo in terms of: •Total time to perform the timed 'up and go' (TUG) test in ambulant participants •Oropharyngeal swallow response (OSR) •Robbins scale","definition_or_measurement_approach":"Between-arm comparisons of TUG time (ambulant participants), OSR, and Robbins scale at Weeks 24, 48, 72."}
• {"endpoint_text":"- 9. Change from Baseline to Weeks 24, 48 and 72 comparing nizubaglustat and placebo in terms of: •The Leeds Sleep Evaluation Questionnaire (LSEQ) •EQ-5D-5L score for participants aged ≥15 years or EQ 5D-Y score for participants aged <15 years •Burden Scale for the Caregiver (BSFC) short version","definition_or_measurement_approach":"Between-arm comparisons of patient-reported outcomes: LSEQ, EQ-5D-5L (≥15y) or EQ-5D-Y (<15y), and BSFC short version at Weeks 24, 48, 72."}
• {"endpoint_text":"- 10. The concentrations of nizubaglustat and its metabolites in cerebrospinal fluid (CSF). The main PK parameters assessed will be: •CSF Cmax and Tmax •CSF Ctrough at Week 72 •AUC0-24 at Baseline •Accumulation ratio for Cmax","definition_or_measurement_approach":"CSF PK sampling to determine CSF Cmax, Tmax, Ctrough at Week 72, AUC0-24 at baseline, and accumulation ratio for Cmax."}
• {"endpoint_text":"- 11. Change from Baseline to Week 72 in GlcCer C16:0; C18:0 concentration in CSF.","definition_or_measurement_approach":"Change from baseline to Week 72 in CSF GlcCer C16:0 and C18:0 concentrations."}
• {"endpoint_text":"- 12. Change from Baseline to Weeks 4, 24, 48 and 72 in the plasma concentrations of: • Glial fibrillary acidic protein (GFAP) • Neurofilament light chain (NfL)","definition_or_measurement_approach":"Change from baseline in plasma GFAP and NfL concentrations at Weeks 4, 24, 48, 72."}
• {"endpoint_text":"- 13. For subprotocol AZA-001-301-NPC only: •\tN-palmitoyl-O-phosphocholinesterase (PPCS) •\tCholestane-3β-5α-6β-triol (C-triol) •\t24(S)-hydroxycholesterol.","definition_or_measurement_approach":"Measurement of disease biomarkers (PPCS, C-triol, 24(S)-hydroxycholesterol) for NPC subprotocol."}
• {"endpoint_text":"- 14. For subprotocol AZA-001-301-GMx only: •\tParticipants with GM1 gangliosidosis - monosialoganglioside GM1 and lyso-monosialoganglioside GM1 •\tParticipants with GM2 gangliosidosis - monosialoganglioside GM2 and lyso-monosialoganglioside GM2.","definition_or_measurement_approach":"Measurement of specified ganglioside biomarkers (GM1/GM2 and lyso- forms) for GMx subprotocol participants."}
• {"endpoint_text":"- 15. Incidence and severity of treatment-emergent adverse events (TEAEs). Change in vital sign parameters, electrocardiogram (ECG) parameters, and laboratory safety parameters from Baseline to each study visit. Incidence of treatment-emergent abnormal laboratory values and ECG abnormalities.","definition_or_measurement_approach":"Safety assessments: incidence/severity of TEAEs, changes in vitals, ECG, labs, and incidence of treatment-emergent lab/ECG abnormalities monitored at each study visit."}

France

Earliest CTIS Part Ii Submission Date

13-12-2024

Latest Decision Or Authorization Date

07-01-2026

Processing Time Days

390

Number Of Sites

1

Number Of Participants

10

Portugal

Earliest CTIS Part Ii Submission Date

20-09-2024

Latest Decision Or Authorization Date

27-11-2025

Processing Time Days

433

Number Of Sites

2

Number Of Participants

10

Germany

Earliest CTIS Part Ii Submission Date

05-12-2024

Latest Decision Or Authorization Date

25-11-2025

Processing Time Days

355

Number Of Sites

1

Number Of Participants

11

Italy

Earliest CTIS Part Ii Submission Date

15-11-2024

Latest Decision Or Authorization Date

25-11-2025

Processing Time Days

375

Number Of Sites

1

Number Of Participants

3

Spain

Earliest CTIS Part Ii Submission Date

08-10-2024

Latest Decision Or Authorization Date

26-12-2025

Processing Time Days

444

Number Of Sites

2

Number Of Participants

15

Sweden

Earliest CTIS Part Ii Submission Date

21-11-2024

Latest Decision Or Authorization Date

25-11-2025

Processing Time Days

369

Number Of Sites

1

Number Of Participants

5

Primary sponsor

Full Name

Azafaros B.V.

Organisation Type

Pharmaceutical company

Country Of Registered Address

Netherlands

Contract research organisations

Name

PPD Development LP

Name

PPD International Holdings LLC

Name

4g Clinical LLC

Third parties

• {"country":"Netherlands","full_name":"Charles River Laboratories Den Bosch B.V.","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"Ireland","full_name":"Signant Health Global Solutions Limited","duties_or_roles":"eCOA and Patient diaries","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"United Biosource LLC","duties_or_roles":"Pharmacovigilance","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Eresearchtechnology Inc.","duties_or_roles":"Cardiac Safety Management, Medical Imaging","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"Centogene GmbH","duties_or_roles":"","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"4g Clinical LLC","duties_or_roles":"","organisation_type":"Non-Pharmaceutical company"}
• {"country":"Belgium","full_name":"PPD International Holdings LLC","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"Australia","full_name":"Redenlab Pty Limited","duties_or_roles":"Video fluoroscopy","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Medidata Solutions Inc.","duties_or_roles":"","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"Scout Clinical","duties_or_roles":"Patient Travel Management","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"United States","full_name":"PPD Development LP","duties_or_roles":"","organisation_type":"Pharmaceutical company"}