E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Atypical Hemolytic Uremic Syndrome |
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E.1.1.1 | Medical condition in easily understood language |
Atypical hemolytic uremic syndrome (aHUS) is a rare syndrome of hemolysis, thrombocytopenia, and renal insufficiency. |
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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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10019515 |
E.1.2 | Term | Hemolytic uremic syndrome |
E.1.2 | System Organ Class | 100000004851 |
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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 effect of ALN-CC5 on platelet response in adult patients with aHUS |
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E.2.2 | Secondary objectives of the trial |
1. To evaluate the effect of ALN-CC5 on hematological response
2. To assess the effect of ALN-CC5 on thrombotic microangiopathy (TMA) response
3. To assess the effect of ALN-CC5 on renal function parameters
4. To evaluate the safety and tolerability of ALN-CC5 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Willing to provide written informed consent and to comply with the study requirements
2. Age 18 years or older
3. Clinical presentation consistent with a diagnosis of primary aHUS
4. Clinical thrombotic microangiopathy (TMA) activity as defined by:
a. Evidence of low platelet count and
b. Evidence of hemolysis and
c. Evidence of impaired renal function
5. ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) >10% (at pre-Screening, Screening, or historically documented in their chart) in a plasma sample that was obtained prior to start of plasma therapy
a. Patients who have already started plasma therapy and who do not have a documented pre-plasma ADAMTS13 result will not be eligible for the study unless they are proven to have a documented aHUS-associated mutation.
6. Women of child-bearing potential must have a negative pregnancy test, cannot be breast feeding, and must be willing to use a highly effective method of contraception
7. Vaccinated with meningococcal group ACWY conjugate vaccine and meningococcal group B vaccine or willingness to receive these vaccinations as well as prophylactic antibiotic treatment for at least 2 weeks after completing the recommended vaccination series or longer, if required by local standard of care.
8. Decision by an independent specialist physician not to treat this patient with eculizumab. The specialist must be independent from this clinical study, have relevant expertise, and document this decision in the patient’s medical records. |
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E.4 | Principal exclusion criteria |
1. Abnormal liver function tests
2. Positive Shiga toxin producing Escherichia coli test
3. Suspected secondary aHUS, in the opinion of the investigator, unless the patient has a documented aHUS-associated genetic mutation.
4. Positive direct Coombs test
5. Prior eculizumab exposure within 3 months
6. Patients considered non-eculizumab responders. except for those with known C5 polymorphisms
7. Patients who have received hemodialysis for >3 months
8. Patients who require hemodialysis or plasma exchange more frequently than every 24 hours
9. Clinical laboratory test results or concomitant conditions considered clinically relevant and unacceptable in the opinion of the Investigator
10. Malignancy (except for non-melanoma skin cancers, cervical in-situ carcinoma, breast
ductal carcinoma in situ, or stage 1 prostate carcinoma) within the last 5 years
11. Patients with active systemic bacterial or fungal infections, as demonstrated by a positive culture result, that require systemic treatment with antibiotics or antifungals
a. Patients receiving empiric or prophylactic antibiotics are not excluded
12. Patients with sepsis or a life-threatening infection
13. Received an investigational agent within the last 90 days or are in follow-up of another clinical study before the first ALN-CC5 administration
14. Active psychiatric disorder, including, but not limited to, schizophrenia, bipolar disorder, or severe depression requiring current pharmacological intervention
15. Patients with aphasia (verbal Glasgow Coma Scale [GCS] score <5 and National
Institutes of Health Stroke Scale [NIHSS] score >0 in item 9)
16. Patients with a reduced level of consciousness (GCS score <14, Restless Leg Syndrome score >1, NIHSS total score ≥1 in item 1)
17. Bone marrow transplant recipients
18. Organ transplant recipients will be excluded, except for kidney transplant recipients with primary aHUS
a. For kidney transplant recipients, primary aHUS will be defined by known genetic mutation and no confounding diagnosis (eg, antibody-mediated rejection or viral infection) by routine kidney biopsy, as judged by the Investigator |
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E.5 End points |
E.5.1 | Primary end point(s) |
Proportion of patients with a platelet response at Week 32, with platelet response defined as platelet count ≥lower limit of normal (LLN) AND no rescue plasma therapy within the preceding 90 days. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Proportion of patients with a hematological response at Week 32, with hematological response defined as the following:
- Platelet count ≥LLN, AND
- Lactate dehydrogenase (LDH) within the normal range, AND
- No rescue plasma therapy within the preceding 90 days
- Proportion of patients with LDH response at Week 32, with LDH response defined as LDH equal to or below the upper limit of normal (ULN) AND no rescue plasma therapy in the preceding 90 days
- Proportion of patients with a complete TMA response at Week 32, with a complete TMA response defined as the following:
- Hematological normalization (defined as platelet count ≥LLN and LDH within the normal range), AND
- Improvement in renal function as demonstrated by ≥25% decrease in serum creatinine from baseline, AND
- No rescue plasma therapy within the preceding 90 days
- Decrease in serum creatinine ≥25% from baseline, assessed over time
- Increase of estimated glomerular filtration rate (eGFR ≥15mL/min/1.73m2 from baseline, assessed over time
- Incidence, severity, and relatedness of adverse events (AEs) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
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 | 1 |
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 | 24 |
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 |
Albania |
Bosnia and Herzegovina |
Canada |
Estonia |
Georgia |
India |
Latvia |
Lithuania |
Macedonia, the former Yugoslav Republic of |
Moldova, Republic of |
Romania |
Serbia |
Sweden |
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E.8.7 | Trial has a data monitoring committee | Yes |
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
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Last patient last visit (safety follow up at week 108). |
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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 | 5 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 0 |