Evaluation of Safety, Tolerability, and Efficacy of Acetylcysteine Amide in Hereditary Cystatin C Amyloid Angiopathy Patients Aged 12 and Older
- Trial ID
- 2023-503969-36-01
- Protocol
- 2023-503969-36-01
- Sponsor
- Arctic Therapeutics hf.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **safety**, tolerability, and efficacy of NPI-001, an oral formulation of acetylcysteine amide, in patients with **Hereditary Cystatin C Amyloid Angiopathy (HCCAA)** aged 12 and over. Additionally, the study aims to assess the effect of NPI-001 on the frequency of cerebral bleeding events. These objectives are clinically relevant as they address the potential therapeutic benefits and risks associated with NPI-001 in managing HCCAA, a condition characterized by amyloid deposition in cerebral vessels leading to hemorrhagic strokes.
Secondary objectives include:
- Assessing the effect of NPI-001 on biomarkers from skin biopsies, including amyloid-cystatin C complexes and related markers.
- Evaluating the severity of cerebral bleeding.
- Characterizing pharmacokinetic parameters of NPI-001 in a subset of participants.
- Assessing the effect of NPI-001 on cognitive status.
- Evaluating the effect on amyloid cystatin C complex aggregation in plasma.
- Assessing the effect on glutathione levels and GSSG/GSH ratios in plasma.
- Evaluating the effect on hCC levels in urine.
- Assessing the effect on death rates compared to historical rates.
Participants
The clinical trial focuses on evaluating the **safety** and tolerability of NPI-001 in patients diagnosed with **Hereditary Cystatin C Amyloid Angiopathy (HCCAA)**. The study population includes both male and female participants aged 12 years and older, specifically of Icelandic ancestry. Participants must have been genotyped or sequenced to confirm the presence of the L68Q mutation in the cystatin C gene. The trial includes individuals with mild cognitive impairment who can adhere to the study protocol. Participants are required to undergo baseline and follow-up skin biopsies, blood tests, and MRI evaluations of the brain. The trial population is selected based on specific genetic and health criteria, and participants must provide informed consent. The sponsor has not provided information regarding the total number of participants in the study.
Plans and Procedures
The clinical trial is designed to evaluate the **safety**, tolerability, and efficacy of the investigational product, acetylcysteine amide, in patients with **Hereditary Cystatin C Amyloid Angiopathy (HCCAA)**. This is a Phase 4, randomized, double-blind, controlled trial. The trial will involve oral administration of the investigational product in tablet form, with a maximum daily dose of 1500 mg and a total treatment period of up to 12 months. The trial is expected to commence recruitment on March 29, 2024, and conclude by March 30, 2025.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, genetic mutation, and cognitive function. The inclusion criteria specify that participants must be of Icelandic ancestry, aged 12 or older, and carry the L68Q mutation in the cystatin C gene. Follow-up visits will occur regularly throughout the study to monitor safety and efficacy endpoints, including treatment-emergent adverse events, vital signs, and the frequency of cerebral bleeding events. Participants will also undergo baseline and follow-up skin biopsies, blood tests, and MRI evaluations of the brain.
The end-of-study visit will assess the primary and secondary endpoints, including the Clinical Dementia Rating (CDR) Scale, levels of cystatin C/amyloid complexes, and plasma concentrations of the investigational product. The expected length of participant involvement is up to 12 months, with conditions for early termination including the occurrence of serious adverse events or withdrawal of consent. Participants are required to adhere to contraception guidelines throughout the study and for four weeks after the last visit. The trial aims to provide valuable insights into the therapeutic potential of acetylcysteine amide in managing HCCAA.
Treatment
The clinical trial involves the administration of the experimental medication **acetylcysteine amide**, also known by its synonyms NACA and N-acetylcysteine amide. This compound is provided in the form of a **tablet** and is intended for oral administration. The maximum daily dose of acetylcysteine amide is 1500 mg, with a total maximum dose of 405,000 mg over the course of the treatment period. The treatment duration is set for a maximum of 12 months. The medication is produced by Arctic Therapeutics EHF and is classified under the ATC codes R05CB01, S01XA08, and V03AB23, indicating its categorization as an acetylcysteine derivative. The chemical origin of the active substance is confirmed, and it is not formulated specifically for pediatric use.
In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on evaluating the safety, tolerability, and efficacy of the experimental drug, acetylcysteine amide, in patients with Hereditary Cystatin C Amyloid Angiopathy (HCCAA). Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen. The trial aims to assess the impact of the medication on the frequency of cerebral bleeding events in the target patient population.
Efficacy
The efficacy of NPI-001 in patients with **Hereditary Cystatin C Amyloid Angiopathy (HCCAA)** will be assessed through a series of primary and secondary endpoints. The primary efficacy endpoint focuses on the frequency of clinical cerebral bleeding events, specifically any bleed that results in stroke, whether hemorrhagic or ischemic. This will be measured throughout the trial to determine the impact of the treatment on reducing such events.
Secondary efficacy endpoints include a variety of clinical and biochemical measures. These encompass the Clinical Dementia Rating (CDR) Scale, which evaluates cognitive function, and the levels of cystatin C/amyloid dimers, oligomers, and polymers compared to monomers. Additionally, the trial will assess levels of glutathione and the GSSG/GSH ratios in plasma, hCC levels in urine, and plasma concentrations of NPI-001, including pharmacokinetic parameters such as Cmax, Tmax, AUC0-24h, and t1/2. The deposition of cystatin C/amyloid protein complexes in the skin, along with skin collagen deposition and cell surface marker activation, will also be evaluated. Furthermore, the clinical impact on speech, paralysis, and symptom reversal speed, as well as CT scans to assess hemorrhage size, distribution, and resolution in the brain, will be considered.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patient is male or female, aged 12 or older, and of Icelandic ancestry (see section 5.1 Selection of Trial Population). Subjects 12-17 years old will only qualify for inclusion if the DSMB approves lowering the minimum age following review of at least 3 months of safety in adults.
- Patient has been genotyped/sequenced and confirmed to carry the L68Q mutation in the cystatin C gene.
- Patients with previously established cystatin C/amyloid protein complexes in the skin
- Patients with mild cognitive impairment with cognitive function to follow the study protocol.
- Patient is willing to have a baseline and follow up skin biopsies according to the schedule of assessments, for up to 12 months, and up to 24 months if participating in the extension phase. *(N/A for patients participating in the additional PK cohort only)
- Patient is willing to have a baseline and follow up blood tests according to the schedule of assessments, for up to 12 months, and up to 24 months if participating in the extension phase. *(N/A for patients participating in the additional PK cohort only)
- Patient is willing to undergo MRI evaluations of the brain. *(N/A for patients participating in the additional PK cohort only)
- Patient has provided informed consent for participation in trial.
- Patient is willing and able to use contraception consistent with local regulations regarding the methods for participants in the clinical trial. Both female participants of childbearing potential and male participants able to father children must have (or have a partner who has) had a bilateral oophorectomy, hysterectomy or bilateral salpingectomy; must abstain from intercourse; or must agree to practice 2 acceptable methods of contraception throughout the course of the study and 4 weeks after the last visit. Acceptable methods of contraception include hormonal contraception (i.e., birth control pills, injected hormones, dermal patch or vaginal ring), intrauterine device, barrier methods (diaphragm, condom), tubal ligation, and vasectomy.
Exclusion Criteria
- Patient does not have L68Q mutation
- Patient is taking medications known to affect or be affected by CYP enzymes or transporters will be excluded to avoid any inference
- Patient has clinically significant illness, mental or physical, that, in the opinion of the investigator, might confound the results of the study, pose additional risk to the patient by their participation, or prevent/impede the patient from completing the study.
- Patient has known sensitivity to NAC
- Subject is not willing to cease NAC supplementation at least 2 weeks prior to study participation.
- Patient is pregnant or breastfeeding.
- Known or suspected excessive alcohol or drug abuse
- There is any concern by the investigator regarding the patient’s safety, compliance, or suitability with respect to his/her participation in the study.
- Use of other investigational drugs at the time of enrollment, or within 5 half-lives of enrollment, or within 14 days, whichever is longer
- Patients with moderate to severe cognitive impairment.
- Coagulation/clotting parameters clinically significant outside the normal range (platelet counts, aPTT, PT
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Iceland | Not Recruiting | 29 Mar 2024 | 25 |