Objectives: The following trial objectives for adolescent patients (from 12 and up to 18 years of age) with plasma therapy-sensitive Atypical Hemolytic-Uremic Syndrome (aHUS) are to:Primary:* Assess the effect of eculizumab on TMA-Event Free status…
ID
Source
Brief title
Condition
- Haemolyses and related conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Endpoint:
* The primary efficacy endpoint for this protocol is TMA-Event Free status
defined as the absence of [1] decrease in platelet count of >25% from the
Platelet Count Pre-PT Baseline Set-Point; [2] PT while the patient is receiving
eculizumab, and
[3] new dialysis for at least 12 weeks in adolescent patients with plasma
therapysensitive Atypical Hemolytic-Uremic Syndrome (aHUS). Dialysis events
occurring within the 14 days after the first dose of Investigational Product
will
not be considered as a new Treatment Period dialysis event. In addition,
dialysis events that commence within the 14 days before the first dose of
Investigational Product and continue up to 14 days after the first dose of
Investigational Product
will not be considered a new Treatment Period dialysis event;
Secondary outcome
Secondary Endpoints:
* TMA Intervention Rate (# PT and # Dialysis Events/Patient/Day) during the
Treatment Period compared with the TMA Intervention Rate prior to the first
dose of Investigational Product;
* Platelet count change from baseline (Platelet Count Pre-PT Baseline Set-Point
value) after first dose of Investigational Product;
* Change in LDH from baseline after first dose of Investigational Product;
* Change in Quality of Life measures * EuroQol 5D from baseline after first
dose of Investigational Product
* Change in renal function parameters as assessed by change in CKD stage from
baseline after the first dose of Investigational Product
* TMA Remission;
* Safety and tolerability of eculizumab;
* PK and PD parameters during induction and maintenance phases of treatment.
Exploratory Endpoints:
* Weekly TMA-related thrombocytopenia resolution rate defined as the absence of
[1] platelet count decrease > 25% from the Platelet Count Pre-PT Baseline Set
Point and [2] platelet count < 150 x 109/L;
Background summary
Because of the severe unmet medical need in the treatment of patients with
this serious and lifethreatening rare disorder, and the demonstrated activity
of eculizumab to reduce thrombotic microangiopathy (TMA); individual physicians
have chosen to utilize eculizumab in the treatment of their severely affected
aHUS patients. To date, there is limited clinical experience in four
therapy-resistant patients, of which one young child, and one therapy-sensitive
patient. These initial results in severely ill aHUS patients have generated the
hypothesis to confirm whether eculizumab treatment will improve the TMA
condition of patients affected by aHUS.
See also page 28 of the protocol ;7.5.1 Eculizumab in aHUS Patients
Study objective
Objectives: The following trial objectives for adolescent patients (from 12 and
up to 18 years of age) with plasma therapy-sensitive Atypical Hemolytic-Uremic
Syndrome (aHUS) are to:
Primary:
* Assess the effect of eculizumab on TMA-Event Free status defined as the
absence of [1] decrease in platelet count of >25% from the Platelet Count
Pre-PT Baseline Set-Point; [2] PT while the patient is receiving eculizumab,
and [3] new
dialysis for at least 12 weeks in adult patients with plasma therapy-sensitive
Atypical Hemolytic-Uremic Syndrome (aHUS).
Secondary:
* Evaluate additional efficacy endpoints such as the effect of eculizumab on:
* TMA Intervention Rate (# PT and # Dialysis Events/Patient/Day) during the
Treatment Period compared with the TMA Intervention Rate prior to the first
dose of Investigational Product.
* Reduction of thrombotic microangiopathy (TMA) as indicated by
thrombocytopenia as measured by platelet count change from baseline through the
treatment period.
* Key Hemolytic measures.
* Quality of Life measures.
* Renal function measures.
* TMA Remission.
* Characterize the overall safety and tolerability of eculizumab.
* Describe the pharmacokinetics (PK) and pharmacodynamics (PD) of eculizumab in
patients with aHUS.
* Perform a series of exploratory efficacy analyses such as the effect of
eculizumab on:
* Platelet count measures.
* Thrombotic measures.
* Pro-inflammatory markers.
* Major Adverse Vascular Events (MAVE).
* Systemic hypertension and anti-hypertensive medication.
* Additional hemolytic measures.
* Additional measures of renal function.
Study design
After screening patient will start with the observation phase and come to the
hospital for a weekly visit for 8 weeks. Patients will be treated with
eculizumab for 26 weeks and will have post-treatment assessments performed at 1
week, 2 weeks, 4 weeks and 8 weeks after the last dose of eculizumab. Total
trial duration for each patient is approximately 35 weeks (3-day Screening
Period, 26 Week Treatment Period, 8-Week Post-Treatment Follow-up Period). The
estimated duration of the study, including an estimated 6 month enrollment
period is approximately 14 months. Patients may be eligible to enroll in an
open-label extension study after completing study evaluations to Week 26.
Patients who prematurely discontinue investigational product during the study
or who do not
enter the extension study will require follow-up contacts for 8 weeks after the
last dose of
eculizumab.
Intervention
Eculizumab 900 mg or 1200 mg will be administered intravenously according to the
following regimens:
* Induction Period: patients will receive eculizumab 900mg via IV infusion over
approximately 35 minutes once a week (every 7 ± 2 days) for 4 weeks followed by
1200mg eculizumab for the 5th dose (7 ± 2 days) later.
* Maintenance Period: patients will receive eculizumab 1200mg via IV infusion
over approximately 35 minutes every two weeks (every 14 ± 2 days).
* If the physician administers plasmapheresis, plasma exchange or FFP, 600 mg
eculizumab must be administered (i) within 60 minutes after each 1 volume
plasmapheresis or plasma exchange and (ii) within 60 minutes prior to each 3
units of FFP infusion, respectively.
Study burden and risks
For most patients, placements of an IV catheter and needle punctures for blood
draws are usually well tolerated. However, they rarely may cause pain,
bleeding, bruising, swelling, clotting, leakage of drug, and possibly infection
at the needle or catheter site.
Patients will receive a vaccine against Neisseria meningitidis that can cause
adverse reactions. Different types of meningococcal vaccines are available. The
study doctor may choose the most appropriate according to the condition.
The electrocardiogram is a painless procedure that traces the activity of the
heart.
Plasma therapy procedures may be performed by your study doctor, at his/her
discretion. The plasma for the transfusion may come from different blood supply
sources depending on the medical institution. Although eculizumab is being
tested for the condition of the patient, there is no guarantee that they will
not be exposed to increased risks of plasma transfusion reactions after being
treated with eculizumab.
54/56 Avenue Hoche
75008 Paris
FR
54/56 Avenue Hoche
75008 Paris
FR
Listed location countries
Age
Inclusion criteria
1. Male or female patients from 12 and up to 18 years of age who have been diagnosed with Atypical Hemolytic-Uremic Syndrome (aHUS).
2. Patients must be receiving PT for aHUS and must be observed to (i) receive *1 PT treatment every two weeks and no more than 3 PT treatments/week (at an unchanged frequency) for at least 8 weeks immediately prior to first dose of Investigational Product and (ii) receive the same volume of PP or PE and units of FFP for at least 8 weeks immediately prior to first dose of Investigational Product.
3. Platelet Count Pre-PT Baseline Set-Point (collected immediately prior to the ualifying PT Episode) is within 75% of the average of the pre-PT platelet counts collected at Screening and during the Observation Period.
4. Known complement regulatory protein genetic abnormality, i.e., a mutation in Complement Protein 3, factor H or associated factor, factor I, or membrane cofactor protein 1 (MCP-1) or known Factor B gainof-function mutation, or known anti-CFH antibody (*aHUS lesions*).
* Patients diagnosed with aHUS with any of these aHUS lesions are eligible and will be assigned to one of the following parallel categories during the treatment period of the trial:
* (Category 1) Complement Protein 3 or factor H or factor I functional deficiency or abnormal factor interaction (C3/CFH/CFI FFP Group);
* (Category 2) Factor B Gain of Function;
* (Category 3) Anti-CFH Antibody (Anti-CFH Group);
* (Category 4) MCP-1 deficiency (MCP-1 Group);
5. Patients diagnosed with HUS of the atypical type without documented complement regulatory protein genetic abnormality or known anti-CFH antibody are eligible if other etiologies of HUS have been ruled out as confirmed in the Exclusion Criteria (i.e., including Shiga-toxin negative, non-infectious, nondrug-exposure-related [e.g., cyclosporine]), no known HIV positivity, and anti-phospholipid antibody
negative). Thrombotic thrombocytopenic purpura also must be ruled out (i.e., ADAMTS-13 activity must be > 5%; see Exclusion Criteria). Patients meeting these conditions will be assigned to Category 5.
In addition, these patients will undergo genetic testing to determine if a mutation can be identified. If a mutation is identified, the patient will be reassigned to the appropriate category.
6. Lactate dehydrogenase (LDH) level * ULN.
7. Creatinine level * ULN for age.
8. Female patients of childbearing potential must be practicing an effective, reliable and medically acceptable contraceptive regimen during the entire duration of the study, including the follow-up period.
9. Patient*s parents/legal guardian must be willing and able to give written informed consent and patients must be willing to give written informed assent (if applicable as determined by the IRB/IEC).
10. Able and willing to comply with study procedures.
Exclusion criteria
1. ADAMTS-13 inhibitor or deficiency (i.e., ADAMTS-13 activity <5%) as measured
at the screening visit.
2. Malignancy.
3. Typical HUS (Shiga toxin +).
4. Known HIV infection.
5. Identified drug exposure-related HUS.
6. Infection-related HUS.
7. Patients with a confirmed diagnosis of sepsis defined as positive blood cultures
within 7 days of the screening visit and not treated with antibiotics to which the
organism is sensitive.
8. Presence or suspicion of active and untreated systemic bacterial infection that, in the opinion of the Investigator confounds an accurate diagnosis of aHUS or impedes the ability to manage the aHUS disease.
9. Pregnancy or lactation.
10. Unresolved meningococcal disease.
11. Known Systemic Lupus Erythematosus (SLE) or antiphospholipid antibody
positivity or syndrome.
12. Any medical or psychological condition that, in the opinion of the investigator, could
increase the patient*s risk by participating in the study or confound the outcome of
the study.
13. Patients receiving IVIg or Rituximab therapy.
14. Patients receiving other immunosuppressive therapies such as steroids, mTOR
inhibitors or FK506 inhibitors are excluded unless: [1] part of a post-transplant antirejection
regime, [2] patient has confirmed anti-CFH antibody requiring
immunosuppressive therapy and [3] dose of such medications have been unchanged
for at least 4 weeks prior to the screening period.
15. Patients receiving Erythrocyte Stimulating Agents (ESAs) unless already on a stable
dose for at least 4 weeks prior to the screening period.
16. Participation in any other investigational drug trial or exposure to other
investigational agent, device, or procedures beginning 4 weeks prior to screening and throughout the entire trial.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2008-006955-28-NL |
| ClinicalTrials.gov | NCT00844428 |
| CCMO | NL27322.091.09 |