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This is a Phase II, open-label study designed to determine if intravenously administered NM8074 results in remission from TMA in treatment-naïve aHUS patients.
The proposed study, NM8074-aHUS-401,will initially assign six (6) patients per cohort in a 2-cohort trial. In the first cohort, we will evaluate a biweekly dosing regimen whereas in the second cohort, we will evaluate a weekly dose (10 mg/kg) followed by the biweekly dose (20 mg/kg) over a 3-month period. These studies will determine if NM8074 results in remission from TMA in aHUS patients. If the study shows efficacy in aHUS, additional patients may be added per cohort.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Cohort 1 | Experimental | 6 subjects will receive an intravenous (IV) infusion of NM8074 at every two weeks for a total of 7 doses |
|
| Cohort 2 | Experimental | 6 subjects will receive weekly doses of 10 mg/kg for a total of 4 doses followed by biweekly doses at 20 mg/kg for a total of 5 doses |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| NM8074 | Drug | NM8074 will be administered as an intravenous infusion. In Cohort 1, all subjects will be administered 20 mg/kg of NM8074 intravenously every two weeks for a total of 7 doses from Day 1 to Day 85 of the Treatment Period. Patients in Cohort 2 will receive weekly doses of 10 mg/kg for a total of 4 doses from Day 1 to Day 22 followed by biweekly doses at 20 mg/kg for a total of 5 doses from Day 29 to Day 85. |
| Measure | Description | Time Frame |
|---|---|---|
| Normalization of platelet count (≥150 x 10^9/L) | Up to Study Day 120 | |
| Normalization of LDH levels to below ULN | Up to Study Day 120 | |
| Normalization of Schistocyte levels (<1%) | Up to Study Day 120 | |
| Change from Baseline or Percent Change from Baseline in renal function | Assessed via the change from baseline or percent change from baseline in serum creatinine level. | Up to Study Day 120 |
| Change from Baseline or Percent Change from Baseline in Haptoglobin | Up to Study Day 120 | |
| Change from Baseline or Percent Change from Baseline in Hemoglobin | Up to Study Day 120 | |
| Change from Baseline or Percent Change from Baseline in proteinuria/creatininuria | Up to Study Day 120 |
| Measure | Description | Time Frame |
|---|---|---|
| Time to achieve complete TMA response | Baseline through Study Day 120 | |
| Time to achieve higher hemoglobin from baseline | Baseline through Study Day 120 | |
| Change from Baseline or Percent Change from Baseline in blood clots |
| Measure | Description | Time Frame |
|---|---|---|
| Change from Baseline or Percent Change from Baseline in CP modulation | Baseline through Study Day 120 | |
| Change from Baseline or Percent Change from Baseline in Factor B levels | Baseline through Study Day 120 |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Rekha Bansal, PhD | Contact | 2164402696 | clinicalsae@novelmed.com |
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| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 34169200 | Background | Barbour T, Scully M, Ariceta G, Cataland S, Garlo K, Heyne N, Luque Y, Menne J, Miyakawa Y, Yoon SS, Kavanagh D; 311 Study Group Members. Long-Term Efficacy and Safety of the Long-Acting Complement C5 Inhibitor Ravulizumab for the Treatment of Atypical Hemolytic Uremic Syndrome in Adults. Kidney Int Rep. 2021 Mar 24;6(6):1603-1613. doi: 10.1016/j.ekir.2021.03.884. eCollection 2021 Jun. | |
| 36329366 |
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| ID | Term |
|---|---|
| D065766 | Atypical Hemolytic Uremic Syndrome |
| ID | Term |
|---|---|
| D006463 | Hemolytic-Uremic Syndrome |
| D014511 | Uremia |
| D007674 | Kidney Diseases |
| D014570 | Urologic Diseases |
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The study will enroll a planned total of 12 patients as subjects for the trial, with extra enrollment if needed, at the discretion of the Investigator. All subjects will be assigned to either Cohort 1 or Cohort 2. Enrollment in Cohort 2 will occur after at least three patients in Cohort 1 have been evaluated for safety for 3 days after the first dose. No more than three patients will be dosed in a day. Safety data will be assessed and reviewed by the Sponsor and Study Investigators for dosed subjects prior to dosing of the rest of the study subjects. In Cohort 1, all 6 subjects will be administered 20 mg/kg of NM8074 intravenously every two weeks for a total of 7 doses. All 6 patients in Cohort 2 will receive weekly doses of 10 mg/kg for a total of 4 doses followed by biweekly doses at 20 mg/kg for a total of 5 doses.
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|
| Up to Study Day 120 |
| Change from Baseline or Percent Change from Baseline in the total number of plasma infusions or exchanges | Baseline through Study Day 120 |
| Change from Baseline or Percent Change from Baseline in eGFR (estimated glomerular filtration rate) | Baseline through Study Day 120 |
| Change from Baseline or Percent Change from Baseline in dialysis requirement | Baseline through Study Day 120 |
| Change from Baseline or Percent Change from Baseline in quality of life (QoL) Assessed via the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale, Version 4. | The FACIT-fatigue scale is a 13-item patient-reported measure of fatigue with a 7-day recall period. Items are scored on a 0 - 4 response scale ranging from "Not at all" to "Very much so". All items are summed to create a single fatigue score with a range from 0 to 52 with a better quality of life indicated by a higher score. | Baseline through Study Day 120 |
| Change from Baseline or Percent Change from Baseline in Quality of Life (QoL) Assessed via the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 Scale (QLQ- C30), Version 3.0 | All EORTC QLQ-C30 scales and single-item measures range from 0 to 100. This includes 3 symptom scales (fatigue, pain, nausea and vomiting), 5 functional scales (physical, role, cognitive, emotional, and social), single-item questions addressing symptoms like insomnia, dyspnea, loss of appetite, and others that are commonly reported by cancer patients, and the perceived financial impact of the disease. A higher score is associated with a greater quality of life for global health status. | Baseline through Study Day 120 |
| Change from Baseline or Percent Change from Baseline in plasma concentration of NM8074 | Baseline through Study Day 120 |
| Maximum plasma concentration (Cmax) | Baseline through Study Day 120 |
| Time corresponding to Cmax (tmax) | Baseline through Study Day 120 |
| Area under the drug concentration-time curves (AUC0-t) | Baseline through Study Day 120 |
| Background |
| Cammett TJ, Garlo K, Millman EE, Rice K, Toste CM, Faas SJ. Exploratory Prognostic Biomarkers of Complement-Mediated Thrombotic Microangiopathy (CM-TMA) in Adults with Atypical Hemolytic Uremic Syndrome (aHUS): Analysis of a Phase III Study of Ravulizumab. Mol Diagn Ther. 2023 Jan;27(1):61-74. doi: 10.1007/s40291-022-00620-3. Epub 2022 Nov 4. |
| 25833956 | Background | Cofiell R, Kukreja A, Bedard K, Yan Y, Mickle AP, Ogawa M, Bedrosian CL, Faas SJ. Eculizumab reduces complement activation, inflammation, endothelial damage, thrombosis, and renal injury markers in aHUS. Blood. 2015 May 21;125(21):3253-62. doi: 10.1182/blood-2014-09-600411. Epub 2015 Apr 1. |
| 33783815 | Background | Pugh D, O'Sullivan ED, Duthie FA, Masson P, Kavanagh D. Interventions for atypical haemolytic uraemic syndrome. Cochrane Database Syst Rev. 2021 Mar 23;3(3):CD012862. doi: 10.1002/14651858.CD012862.pub2. |
| D052776 |
| Female Urogenital Diseases |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D052801 | Male Urogenital Diseases |
| D000743 | Anemia, Hemolytic |
| D000740 | Anemia |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D057049 | Thrombotic Microangiopathies |
| D013921 | Thrombocytopenia |
| D001791 | Blood Platelet Disorders |
| D000095542 | Cytopenia |