| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Paroxysmal Nocturnal Hemoglobinuria (PNH) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Rare blood disorder that causes red blood cells to break down earlier than they should |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10055629 |
| E.1.2 | Term | Paroxysmal nocturnal hemoglobinuria |
| E.1.2 | System Organ Class | 100000004857 |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the efficacy of ACH-0144471 plus eculizumab based on the increase in hemoglobin (Hgb) relative to baseline during 24 weeks of treatment |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the efficacy of ACH-0144471 plus eculizumab based on the reduction in the number of RBC units transfused during the 24 weeks of treatment with ACH-0144471 compared to the 24 weeks prior to initiation of treatment with ACH-0144471
• To evaluate the efficacy of ACH-0144471 plus eculizumab based on the percentage of patients who are RBC transfusion-independent during 24 weeks of treatment
• To evaluate the efficacy of ACH-0144471 plus eculizumab based on the change from baseline in lactate dehydrogenase (LDH) during 24 weeks of treatment
• To evaluate the safety and tolerability of 24 weeks of treatment with ACH-0144471 plus eculizumab based on serious adverse events (SAEs), Grade 3 and Grade 4 adverse events (AEs), and events leading to discontinuation of study drug |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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
|
|
| E.4 | Principal 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 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• For the Optimal Dose Group: median Hgb during the 24-week treatment phase compared to the baseline (Day 1) Hgb
• For the groups treated at doses lower than the optimal dose level: median Hgb over the time period that the patient received the highest dose level during the 24-week treatment phase compared to baseline (Day 1) Hgb |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• Number of units of RBCs transfused during 24 weeks of treatment
• RBC transfusion status: number and percent of patients without RBC transfusions during 24 weeks of treatment
• Change from baseline in LDH during 24 weeks of treatment
• Evaluate safety and tolerability during 24 weeks of treatment based on SAEs, Grade 3 and Grade 4 AE, and events leading to discontinuation of study drug. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 3 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| United States |
| Italy |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
This study includes a long-term extension; therefore after 24 weeks subjects may continue with treatment for an undetermined amount of time.
LVLS may not be equal to 24weeks+taper+follow-up. Analysis is defined to 24 weeks.
|
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
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