Thrombotic Microangiopathies
Conditions
Brief summary
Multicentre Study of nomacopan in Paediatric Haematopoietic Stem-Cell Transplant Associated Thrombotic Microangiopathy
Detailed description
This is an open-label, multi-centre study of two-parts, Part A and B, includes 24 weeks of treatment, safety follow up after 30 days. Part A: dose algorithm, safety and efficacy Part B: safety and efficacy
Interventions
The study population will consist of paediatric patients who have undergone allogeneic or autologous HSCT and develop HSCT-TMA within a year of HSCT
Sponsors
AKARI Therapeutics
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Open-label, uncontrolled, multi-centre two-part study. Part A: dose algorithm, safety and efficacy Part B: safety and efficacy
Eligibility
Sex/Gender
ALL
Age
6 Months to 18 Years
Healthy volunteers
No
Inclusion criteria
1. Aged ≥ 0.5 and \< 18 years at the time of diagnosis of TMA. 2. Undergone allogeneic or autologous HSCT. 3. TMA diagnosis within a year of their allogeneic or autologous HSCT. 4. Clinical or histological diagnosis of TMA 5. Provision of written informed consent. 6. Provision of informed assent
Exclusion criteria
1. Patients weighing less than 5 kg. 2. Patients with a positive direct Coombs' test. 3. Patients who do not receive nomacopan within 21 days of the initial diagnosis of TMA. 4. Patients having an active systemic or organ system bacterial or fungal infection or progressive severe infection at the time of diagnosis of TMA 5. Grade 4 Acute graft-versus-host disease (GVHD) 6. Received eculizumab or any other complement blocker therapy at any time. 7. Known hypersensitivity to the active ingredient or excipients If an enrolled patient has a positive ADAMTS13 test (\<10%) returned from their screening assessment, the patient should be withdrawn from the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants NOT Requiring a Red Blood Bell Transfusion (Transfusion Independence) for 28 Days or More OR Number of Participants With a Urine Protein Creatinine Ratio Value of ≤ 2 mg/mg Maintained for 28 Days or More. | 24 weeks | Red blood cell transfusion independence for ≥28 days immediately prior to any scheduled clinical visit up to Week 24 or Urine protein creatinine ratio ≤ 2 mg/mg maintained over ≥ 28 days immediately prior to any scheduled clinical visit up to week 24 Transfusion independence is defined as no RBC transfusion attributable to, or required to manage, thrombotic microangiopathy (TMA). Transfusions required for causes other than TMA will not be considered within the evaluation of the efficacy endpoints. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With a Normalised sC5b-9 Value (Where sC5b-9 is the Same Value as the Upper Limit of Normal or Less) | 24 weeks | Plasma sC5b-9 ≤ upper limit of normal (ULN) |
| Number of Participants With a Normalised Lactate Dehydrogenase (LDH) Value (Where LDH is the Same Value as the Upper Limit of Normal or Less) | 24 weeks | Lactate dehydrogenase (LDH) ≤ULN |
| Normalisation of Lab Parameters | 24 weeks | Number of participants with a normalised haptoglobin value (where haptoglobin is within the normal ranges) |
| Number of Participants Not Requiring a Platelet Transfusion (Transfusion Independence) for 28 Days or More. | 24 weeks | Transfusion independence is defined as no platelet transfusion attributable to, or required to manage, thrombotic microangiopathy (TMA). Transfusions required for causes other than TMA will not be considered within the evaluation of the efficacy endpoints. |
Countries
Poland, United Kingdom, United States
Participant flow
Recruitment details
The study population consists of paediatric patients who have undergone allogeneic or autologous haematopoietic stem cell transplantation (HSCT) and developed haematopoietic stem cell transplant associated thrombotic microangiopathy (HSCT-TMA) within a year of HSCT
Participants by arm
| Arm | Count |
|---|---|
| Nomacopan The trial was a 24-week open-label, non-comparative study in paediatric patients with HSCT-TMA.
Patients will be given an ablating dose on Day 1, 12 hours apart which was determined by the child's weight on Day 1:
Ablating Dose:
* 0.5 to \< 2 years =1.7 mg/kg
* 2 to \< 9 years =1.3 mg/kg
* 9 to \< 18 years =1.0 mg/kg
For children in the youngest two cohorts (≥ 0.5 to \< 2 years, and ≥ 2 to \< 9 years), the dose was re-calculated at the week 8 and week 16 visits using the child's new weight measured at that visit.
The starting maintenance dose, administered 12 hours apart, from Day 2 until the end of treatment was 0.30 mg/kg for all 3 age groups.
If required, from pre-dose Day 7 onwards, a dose escalation was permitted if the CH50 results were \> 10 U Eq/mL and/or the unbound nomacopan in serum was \< 55 ng/mL.
Two dose escalations were permitted - an increase from the maintenance dose of 0.30 mg/kg to 0.45 mg/kg with a further increase to 0.60 mg/kg if required. Dose increases were preceded by an ablating dose as determined by age as per Day 1. | 10 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 4 |
Baseline characteristics
| Characteristic | Nomacopan |
|---|---|
| Age, Customized ≥ 0.5 to < 2 years | 1 Participants |
| Age, Customized ≥ 2 to < 9 years | 3 Participants |
| Age, Customized ≥ 9 to < 18 years | 6 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 9 Participants |
| Region of Enrollment United Kingdom | 9 participants |
| Region of Enrollment United States | 1 participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 0 / 3 | 0 / 6 | 4 / 10 | 0 / 3 | 0 / 0 |
| other Total, other adverse events | 0 / 1 | 1 / 3 | 1 / 6 | 7 / 10 | 2 / 3 | 0 / 0 |
| serious Total, serious adverse events | 0 / 1 | 0 / 3 | 0 / 6 | 6 / 10 | 2 / 3 | 0 / 0 |
Outcome results
Primary
Number of Participants NOT Requiring a Red Blood Bell Transfusion (Transfusion Independence) for 28 Days or More OR Number of Participants With a Urine Protein Creatinine Ratio Value of ≤ 2 mg/mg Maintained for 28 Days or More.
Red blood cell transfusion independence for ≥28 days immediately prior to any scheduled clinical visit up to Week 24 or Urine protein creatinine ratio ≤ 2 mg/mg maintained over ≥ 28 days immediately prior to any scheduled clinical visit up to week 24 Transfusion independence is defined as no RBC transfusion attributable to, or required to manage, thrombotic microangiopathy (TMA). Transfusions required for causes other than TMA will not be considered within the evaluation of the efficacy endpoints.
Time frame: 24 weeks
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Nomacopan | Number of Participants NOT Requiring a Red Blood Bell Transfusion (Transfusion Independence) for 28 Days or More OR Number of Participants With a Urine Protein Creatinine Ratio Value of ≤ 2 mg/mg Maintained for 28 Days or More. | RBC transfusion independent for ≥ 28 days | 2 Participants |
| Nomacopan | Number of Participants NOT Requiring a Red Blood Bell Transfusion (Transfusion Independence) for 28 Days or More OR Number of Participants With a Urine Protein Creatinine Ratio Value of ≤ 2 mg/mg Maintained for 28 Days or More. | Urine protein creatinine ratio (UPCR) ≤ 2 mg/mg for ≥ 28 days | 4 Participants |
Secondary
Normalisation of Lab Parameters
Number of participants with a normalised haptoglobin value (where haptoglobin is within the normal ranges)
Time frame: 24 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Nomacopan | Normalisation of Lab Parameters | 4 Participants |
Secondary
Number of Participants Not Requiring a Platelet Transfusion (Transfusion Independence) for 28 Days or More.
Transfusion independence is defined as no platelet transfusion attributable to, or required to manage, thrombotic microangiopathy (TMA). Transfusions required for causes other than TMA will not be considered within the evaluation of the efficacy endpoints.
Time frame: 24 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Nomacopan | Number of Participants Not Requiring a Platelet Transfusion (Transfusion Independence) for 28 Days or More. | 0 Participants |
Secondary
Number of Participants With a Normalised Lactate Dehydrogenase (LDH) Value (Where LDH is the Same Value as the Upper Limit of Normal or Less)
Lactate dehydrogenase (LDH) ≤ULN
Time frame: 24 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Nomacopan | Number of Participants With a Normalised Lactate Dehydrogenase (LDH) Value (Where LDH is the Same Value as the Upper Limit of Normal or Less) | 2 Participants |
Secondary
Number of Participants With a Normalised sC5b-9 Value (Where sC5b-9 is the Same Value as the Upper Limit of Normal or Less)
Plasma sC5b-9 ≤ upper limit of normal (ULN)
Time frame: 24 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Nomacopan | Number of Participants With a Normalised sC5b-9 Value (Where sC5b-9 is the Same Value as the Upper Limit of Normal or Less) | 10 Participants |