Safety, Tolerability and Efficacy of NPI-001 in Patients With Hereditary Cystatin C Amyloid Angiopathy (HCCAA) (HCCAA)

The study aims to measure safety, tolerability and biomarker-based efficacy of NPI-001 (AT-001) in Subjects with Hereditary Cystatin C Amyloid Angiopathy (HCCAA). In the study participants receive increasing dose or active treatment (250 mg vs 500mg vs 750 mg) or matched placebo in the form of tablets BID.

Study Overview

• Status: Active, not recruiting
• Conditions: Hemorrhage Brain; Hemorrhage Cerebral; Hereditary Cystatin C Amyloid Angiopathy (HCCAA)
• Intervention / Treatment: Drug: NACA

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 2

Contacts and Locations

Study Locations

• Iceland
  • Reykjavik, Iceland, 108
    • Landspitali University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. 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.
2. Patient has been genotyped/sequenced and confirmed to carry the L68Q mutation in the cystatin C gene.
3. Patients with previously established cystatin C/amyloid protein complexes in the skin
4. Patients with mild cognitive impairment with cognitive function to follow the study protocol.
5. 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.*
6. 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.*
7. Patient is willing to undergo MRI evaluations of the brain.*
8. Patient has provided informed consent for participation in trial.
9. 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:

1. Patient does not have L68Q mutation.
2. Patients with moderate to severe cognitive impairment.
3. 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.
4. Patient has known sensitivity to NAC
5. Coagulation/clotting parameters clinically significant outside the normal range (platelet counts, aPTT, PT)
6. Subject is not willing to cease NAC supplementation at least 2 weeks prior to study participation.
7. Patient is pregnant or breastfeeding.
8. Known or suspected excessive alcohol or drug abuse.
9. There is any concern by the investigator regarding the patient's safety, compliance, or suitability with respect to his/her participation in the study.
10. Use of other investigational drugs at the time of enrollment, or within 5 half-lives of enrollment, or within 14 days, whichever is longer.
11. Patient is taking medications known to affect or be affected by CYP enzymes or transporters will be excluded to avoid any inference.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Landspitali University Hospital; All participants receive active treatment in the form of tablets administered twice per day.	Drug: NACA; 250 mg tablets BID, increasing dosage from 250 mg BID to 750 mg BID; Other Names: AT-001; NAC-amid

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Treatment-Emergent Adverse Events	Incidence of Treatment-Emergent Adverse Events in response to NPI-001 (AT-001) administered orally in subjects with HCCAA. Assessment of the number of participants with treatment-related adverse events. Assessment of the amount of mild and severe adverse events related to the treatment.	Through study completion, up to 24 months
Frequency of cerebral bleeding events	Assessment of frequency of clinical cerebral bleedings events, defined as any bleed that causes stroke, hemorrhagic or ischemic after 12 months of treatment (main study) and after 24 months of treatment (12 - months study extension phase)	Through study completion, up to 24 months
Safety labs results within normal range	Safety labs result not being outside of normal ranges and/or not clinically significant as assessed by the PI.	Through study completion, up to 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biomarker - cystatin C aggregation in the skin	Reduction in amyloid-cystatin C complexes in skin biopsies compared with baseline levels based on % of area stained using Immunohistochemistry	Through study completion, up to 24 months

Collaborators and Investigators

• Sponsor: Arctic Therapeutics

Publications and helpful links

General Publications

• March ME, Gutierrez-Uzquiza A, Snorradottir AO, Matsuoka LS, Balvis NF, Gestsson T, Nguyen K, Sleiman PMA, Kao C, Isaksson HJ, Bragason BT, Olafsson E, Palsdottir A, Hakonarson H. NAC blocks Cystatin C amyloid complex aggregation in a cell system and in skin of HCCAA patients. Nat Commun. 2021 Mar 23;12(1):1827. doi: 10.1038/s41467-021-22120-4.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): April 3, 2024
• Primary Completion (Estimated): December 29, 2026
• Study Completion (Estimated): January 31, 2027

Study Registration Dates

• First Submitted: March 18, 2026
• First Submitted That Met QC Criteria: July 16, 2026
• First Posted (Actual): July 21, 2026

Study Record Updates

• Last Update Posted (Actual): July 21, 2026
• Last Update Submitted That Met QC Criteria: July 16, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: CAA; HCCAA; rare dementia; familial dementia; cystatin C amyloid angiopathy
• Additional Relevant MeSH Terms: Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Mental Disorders; Pathologic Processes; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Neurocognitive Disorders; Hemorrhage; Proteostasis Deficiencies; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Intracranial Arterial Diseases; Cerebral Arterial Diseases; Cerebral Small Vessel Diseases; Amyloidosis, Familial; Amyloidosis; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Cerebral Amyloid Angiopathy; Dementia; Cerebral Hemorrhage; Intracranial Hemorrhages; Cerebral Amyloid Angiopathy, Familial; caficrestat
• Other Study ID Numbers: AT-23-01; 2023-503969-36-01 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No