Evaluation of Acetylcysteine Amide in Hereditary Cystatin C Amyloid Angiopathy: Safety, Tolerability, and Efficacy in Patients Aged 12 and Older
- Trial ID
- 2023-503969-36-00
- Protocol
- 2023-503969-36-00
- 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. This includes assessing the effect of NPI-001 on the frequency of cerebral bleeding events compared to historical rates, as well as its impact on biomarkers from skin biopsies, specifically the reduction of amyloid-cystatin C complexes and related collagen and skin cell surface activation markers. These objectives are clinically relevant as they aim to address the critical aspects of disease management and potential therapeutic benefits in HCCAA, a condition characterized by cerebral amyloid angiopathy leading to recurrent brain hemorrhages.
Secondary objectives include:
- Assessing the effect of NPI-001 on cognitive status.
- Evaluating the impact on death rates in comparison with historical rates.
- Investigating the effect on amyloid cystatin C complex aggregation in plasma.
- Assessing changes in glutathione levels and GSSG/GSH ratios in plasma.
- Evaluating hCC levels in urine.
- Using MRI imaging to assess amyloid deposition in the brain.
- Characterizing pharmacokinetic parameters of NPI-001 in a subset of participants with HCCAA.
Participants
The clinical trial involves participants diagnosed with **Hereditary Cystatin C Amyloid Angiopathy (HCCAA)**, a rare genetic condition. The study population includes both male and female subjects aged 12 and older, with a specific focus on individuals of Icelandic ancestry. Participants must have been genotyped to confirm the presence of the L68Q mutation in the cystatin C gene. The trial population is selected based on their willingness to undergo various assessments, including skin biopsies, blood tests, and MRI evaluations, over a period of up to 12 months. Participants are required to adhere to local contraception regulations throughout the study. The trial includes individuals with mild cognitive impairment, provided they can follow the study protocol. The sponsor has not provided information regarding the total number of participants in the trial.
Plans and Procedures
The clinical trial is designed to evaluate the **safety**, tolerability, and efficacy of the investigational product, acetylcysteine amide, in patients diagnosed 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 conclude by December 30, 2024, with recruitment having commenced on September 29, 2023.
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 willingness to undergo specific assessments. Follow-up visits will occur regularly to monitor treatment-emergent adverse events, serious adverse events, and changes in vital signs, ECG, and laboratory tests. The primary endpoints include the assessment of safety and the reduction of skin deposition of cystatin C/amyloid protein complexes. Secondary endpoints will evaluate clinical dementia ratings, plasma concentrations of the investigational product, and changes in amyloid deposition in the brain.
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 will also be required to adhere to contraception guidelines throughout the study and for four weeks after the last visit. The end-of-study visit will involve final assessments to evaluate the overall impact of the treatment on the primary and secondary endpoints. The trial aims to provide comprehensive data on the investigational product's efficacy and safety profile in the target population.
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 chemically derived and is provided in the form of a **tablet**. The medication is identified by the sponsor product code NPI-001 and is manufactured by Arctic Therapeutics EHF. The **route of administration** is oral, with a maximum daily dose of 1500 mg and a total maximum dose of 405,000 mg over a treatment period of up to 12 months. The medication is not formulated specifically for pediatric use and is not classified as an orphan drug. The **ATC codes** associated with acetylcysteine amide are R05CB01, S01XA08, and V03AB23, indicating its classification under mucolytics, ophthalmologicals, and antidotes, respectively.
In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on the administration of the experimental medication, acetylcysteine amide. 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 safety, tolerability, and efficacy of NPI-001 in patients with Hereditary Cystatin C Amyloid Angiopathy (HCCAA), with specific objectives including the evaluation of cerebral bleeding events and biomarker changes from skin biopsies.
Efficacy
Efficacy in the clinical trial evaluating NPI-001 (acetylcysteine amide) for patients with **Hereditary Cystatin C Amyloid Angiopathy (HCCAA)** will be assessed through several primary and secondary endpoints. The primary efficacy endpoints include the evaluation of skin deposition of cystatin C/amyloid protein complexes, focusing on the ratios of monomers versus dimers and other high-molecular-weight versions, as well as skin collagen deposition and cell surface marker activation, such as vimentin and SMAD/WNT-1. These parameters will be measured using cryoEM and Western blot techniques. Additionally, the frequency of serious cerebral bleeding events will be compared to historical rates.
Secondary efficacy endpoints will include assessments using the Clinical Dementia Rating (CDR) Scale, monitoring of deaths, and analysis of levels of cystatin C/amyloid dimers, oligomers, and polymers versus monomers. Plasma levels of glutathione and GSSG/GSH ratios, hCC levels in urine, and plasma concentrations of NPI-001 will also be measured. Changes in amyloid deposition in the brain will be evaluated. These assessments will be conducted at various timepoints throughout the trial, with specific schedules for skin biopsies, blood tests, and MRI evaluations as outlined in the trial protocol.
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.
- Patient is willing to have a baseline and follow up skin biopsies according to the schedule of assessments, for up to 12 months.
- Patient is willing to have a baseline and follow up blood tests according to the schedule of assessments, for up to 12 months.
- Patient is willing to undergo MRI evaluations of the brain.
- 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.
- 2.3. Patients with mild cognitive impairment with cognitive function to follow the study protocol.
Exclusion Criteria
- Patient does not have L68Q mutation
- 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
- 1.2. Patients with moderate to severe cognitive impairment.
- Patient is taking medications known to affect or be affected by CYP enzymes or transporters will be excluded to avoid any inference
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Iceland | Not Yet Recruiting | 29 Sept 2023 | 25 |