A treatment study of ACH-0144471 in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) Who Have poor Response to Eculizumab Monotherapy

Phase 1

• Conditions: MedDRA version: 21.1Level: LLTClassification code 10055629Term: Paroxysmal nocturnal hemoglobinuriaSystem Organ Class: 100000004857; Paroxysmal Nocturnal Hemoglobinuria (PNH); Therapeutic area: Diseases [C] - Blood and lymphatic diseases [C15]

• Registration Number: EUCTR2016-003526-16-GB
• Lead Sponsor: Alexion Pharmaceuticals Inc.

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2018-04-23
• Last Update Posted: 5 January 2021

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 14

Inclusion Criteria

1. Diagnosed with PNH
2. Have received at least one RBC transfusion within 12 weeks prior to screening
3. Anemia (Hgb <10 g/dL) with adequate reticulocytosis (absolute reticulocyte count = 100 x 10^9/L)
4. Must be on a stable regimen of eculizumab (have been on eculizumab for at least 24 weeks without change in dose or schedule for at least the past 12 weeks)
5. Platelet count = 40,000/µL without the need for platelet transfusions
6. Documentation of vaccination for N. meningitidis, H. influenzae, and S. pneumoniae, or willingness to receive vaccinations as described in Section 6.3
7. Willingness to receive antibiotic prophylaxis if not already prescribed within standard of care, as described in Section 5.2.3
8. Age 18 years to 65 years, inclusively (or = minimum adult age in accordance with local legal requirements)
9. Female participants of childbearing potential must agree to use an acceptable method of contraception (as defined in Section 5.5.5) from the date of signing the informed consent to the first day of dosing (Day 1), and must agree to use a highly effective method of contraception (as defined in Section 5.5.5) from the first day of dosing to 30 days after their last dose of study drug. Female participants of childbearing potential must also have a negative serum pregnancy test during Screening and negative urine pregnancy test on Day 1.
Female participants of non-childbearing potential need not employ a method of contraception.
10. Non-sterile male participants must agree to use a highly effective method of contraception (as defined in Section 5.5.5) with their partner(s) of childbearing potential from the first day of dosing to 90 days after their last dose of study drug.
Males who are surgically sterile need not employ additional contraception.
Males must agree not to donate sperm while enrolled in this study and for 90 days after their last dose of study drug.
11. Must agree to provide written informed consent
12. Must be willing and able, at all times, to have transportation and telephone access, and to be within 1 hour of an emergency medical center

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 14
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion Criteria

1. Current evidence of bone marrow failure or aplastic anemia requiring treatment
2. History of a major organ transplant (e.g., heart, lung, kidney, liver) or hematopoietic stem cell/marrow transplant (unless HSCT engraftment has failed)
3. Received another investigational agent within 30 days or 5 half-lives of the investigational agent prior to study entry, whichever is greater
4. Documented C5 mutations
5. Known or suspected complement deficiency
6. Contraindication to one or more of the required vaccinations
7. Active bacterial infection or clinically significant active viral infection, a body temperature >38°C, or other evidence of infection on Day 1, or have a history of febrile illness within 14 days prior to first study drug administration
8. History of meningococcal infection, or a first-degree relative or household contact with a history of meningococcal infection
9. History of hypersensitivity reactions to commonly used antibacterial agents, including beta-lactams, penicillin, aminopenicillins, fluoroquinolones (specifically including ciprofloxacin), cephalosporins, and carbapenems, which in the opinion of the PI would make it difficult to properly provide prophylactic antibiotic therapy or treat an active infection.
10. History or presence of any clinically relevant co-morbidities that would make the patient inappropriate for the study (for example, is likely to result in deterioration of the patient’s condition, affect the patient’s safety during the study, or confound the results of the study)
11. Laboratory abnormalities at screening, including:
• Alkaline phosphatase (ALP) > 1.5 X upper limit of normal (ULN)
• Absolute neutrophil counts (ANC) <1,000/µL
• Alanine aminotransferase (ALT) > 1.5 ULN
• Direct bilirubin > 1.5 X ULN (unless due to extravascular hemolysis, in the opinion of the investigator)
• Any other clinically significant laboratory abnormality that, in the opinion of the Principal Investigator (PI), would make the patient inappropriate for the study or put the patient at undue risk
12. Females who are pregnant, nursing, or planning to become pregnant during the study or within 90 days of study drug administration
13. Prior history or current evidence of biliary cholestasis
14. Gilbert’s syndrome
Patients with history or family history suggestive of Gilbert’s syndrome will be tested and excluded from study if positive for UGT1A1 genotyping polymorphism or missense change
15. Evidence of human immunodeficiency virus (HIV), hepatitis B or hepatitis C infection (positive serology for HIV-1 antibody [HIV Ab], positive hepatitis B surface antigen [HbsAg], or positive anti-HCV antibody [HCV Ab] at Screening or historically
16. Taking medications known to prolong the QT/QTc interval (see Section 5.5.2), or have a family history of prolonged QT syndrome or with a screening QTcF >450 msec for males or > 470 msec for females
17. Have eGFR< 30 mL/min/1.73 m^2 and/or are on dialysis

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified