Renal AL Amyloid Involvement and NEOD001 (RAIN)

• ClinicalTrials.gov Identifier: NCT03168906
• Recruitment Status: Terminated
• First Posted: May 30, 2017
• Results First Posted: December 24, 2019
• Last Update Posted: September 9, 2020
• Sponsor: Tufts Medical Center
• Information provided by (Responsible Party): Tufts Medical Center

Study Description

Brief Summary:

This is a multicenter, Phase 2b, randomized, double-blind, placebo-controlled, two-arm, parallel-group efficacy and safety study of NEOD001 as a single agent administered intravenously in adults with AL amyloidosis who have a maintained hematologic response to their most recent treatment for AL amyloidosis (e.g., chemotherapy, autologous stem cell transplant [ASCT]) and have persistent renal dysfunction.

Condition or disease	Intervention/treatment	Phase
Amyloidosis	Drug: NEOD001; Drug: Placebo	Phase 2

Detailed Description:

This is a multicenter, Phase 2b, randomized, double-blind, placebo-controlled, two-arm, parallel-group efficacy and safety study of NEOD001 as a single agent administered intravenously in adults with AL amyloidosis who have a maintained hematologic response to their most recent treatment for AL amyloidosis (e.g., chemotherapy, autologous stem cell transplant [SCT]) and have persistent renal dysfunction. Subject screening will occur during the 28 days prior to the first administration of study drug (i.e. month 1 day 1). If screening assessments are completed and all eligibility requirements are met, the subject will be enrolled. Study visits will occur every 28 days based on scheduling from month 1 day 1. A ±5-day window is allowed for visits starting after month 1. Subjects may receive up to 12 infusions of study drug. Subjects who discontinue study drug before the initial End of Study (EOS) visit should have an Early Treatment Discontinuation (ETD) Visit 30 (±5) days after their final administration of study drug. After completing 12 months of treatment and the confirmatory EOS visit, a subject may enter an open-label extension (OLE) study, during which subjects will receive active treatment with NEOD001 for 12 months and may receive concurrent chemotherapy.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 12 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: The RAIN Study, a Multicenter Randomized Double-blind Phase 2b Study of NEOD001 in Previously Treated Subjects With Systemic Light-chain (AL) Amyloidosis and Persistent Renal Involvement
• Actual Study Start Date: July 5, 2017
• Actual Primary Completion Date: April 23, 2018
• Actual Study Completion Date: February 6, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: NEOD001; Study Drug given IV every 28 days at 24mg/kg	Drug: NEOD001; NEOD001 is a monoclonal antibody directed at soluble and insoluble light chain aggregates
Placebo Comparator: Placebo; Placebo	Drug: Placebo; Saline bag

Outcome Measures

Primary Outcome Measures :

1. Confirmed Renal Response After Treatment With NEOD001 [ Time Frame: Baseline to 13 Months ]
   A renal response is a ≥ 30% reduction in proteinuria in the absence of a ≥ 25% decrease in eGFR. A confirmed renal response is one that has been documented as present one month after 12 monthly treatments.

Secondary Outcome Measures :

1. Measured GFR at Study Entry [ Time Frame: Baseline ]
   The aim of this study is to assess the performance of CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) creatinine in comparison to iothalamate clearance measured in AL amyloidosis patients. Iothalamate will be given subcutaneously. Urine and plasma samples will then be obtained. All laboratory tests for samples obtained for GFR measurement will be performed at Mayo Clinic Rochester. Quantification of iothalamate in urine and plasma will be performed using a tandem mass spectrometric method.
2. Time to CKD 4 or 5 [ Time Frame: Baseline to 13 Months ]
   Months to Chronic Kidney Disease level 4 or 5
3. Time to eGFR ≤ 15 or Dialysis [ Time Frame: Baseline to 13 Months ]
   Months to estimated Glomerular Filtration Rate ≤ 15 or dialysis
4. Time to Doubling of Creatinine [ Time Frame: Baseline to 13 Months ]
   Months to doubling of serum creatinine
5. Time to ≥ 40% Reduction in eGFR [ Time Frame: Baseline to 13 Months ]
   Months to ≥ 40% reduction in estimated glomerular filtration rate
6. Renal Response in Patients With Maintained Hematologic Responses After 24 Monthly Treatments. [ Time Frame: Baseline to 26 months ]
   A renal response is a ≥ 30% decrease in proteinuria or drop of proteinuria below 0.5 g/24h in the absence of renal progression.
7. All Cause of Mortality at 26 Months [ Time Frame: Baseline to 26 months ]
   Death at 26 months from Baseline due to any cause

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. 18 years of age or older
2. Biopsy-proven diagnosis of AL amyloidosis by immunohistochemistry or mass spectroscopy of a tissue biopsy excluding bone marrow
3. Screening renal biopsy for RAIN confirming AL amyloidosis as exclusive or dominant cause of renal damage
4. Persistent renal involvement from diagnosis with proteinuria (predominantly albumin) > 500mg/day in a 24-hour urine collection
5. CKD 1 to 3 (eGFR > 30)
6. ≥1 prior systemic hematologic therapy for a free light chain (FLC) producing hematologic malignancy underlying the initial diagnosis of AL amyloidosis with at least a partial FLC response (PR, VGPR, CR) to treatment deemed stable and not requiring further treatment
7. ECOG Performance Status ≤ 2

8. Clinical laboratory values:

   1. Absolute neutrophil count > 1000/μL
   2. Platelet count > 75,000/μL
   3. Total bilirubin ≤ 1.5X ULN
   4. Alkaline phosphatase ≤ 5X ULN
   5. NT-proBNP < 1800 pg/mL
9. Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care

Exclusion Criteria:

1. Amyloidosis due to mutations of the transthyretin gene or presence of other non-AL amyloidosis
2. Female patients who are lactating, breastfeeding, or pregnant
3. Patients who have not been treated or who have received chemotherapy within 6 months, or SCT within 12 months, for the light-chain producing hematologic disease causing AL amyloidosis, at the time of the first dose of NEOD001 (month 1 day 1)
4. Patients who at initial diagnosis or later met the International Myeloma Working Group (IMWG) definition of active multiple myeloma requiring therapy (Appendix 3)
5. Patients whose screening renal biopsies for RAIN show dominant causes of renal damage not related to AL amyloidosis
6. Medically documented cardiac syncope, uncompensated congestive heart failure, myocardial infarction within the previous 6 months, unstable angina pectoris, clinically significant repetitive atrial or ventricular arrhythmias despite antiarrhythmic treatment, or severe orthostatic hypotension or clinically significant uncompensated autonomic insufficiency
7. Comorbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens
8. Ongoing or active infection, known HIV positive, known to be hepatitis B surface antigen-positive or has known or suspected active hepatitis C infection.
9. Psychiatric illness/social situations that would limit compliance with study requirements

Contacts and Locations

Locations

United States, Arizona

Mayo Clinic- Arizona

Scottsdale, Arizona, United States, 85259

United States, California

University of California San Francisco

San Francisco, California, United States, 94143

United States, Florida

Mayo Clinic- Florida

Jacksonville, Florida, United States, 32224

United States, Massachusetts

Tufts Medical Center

Boston, Massachusetts, United States, 02111

United States, Michigan

Karmanos Cancer Institute

Detroit, Michigan, United States, 48201

United States, Minnesota

Mayo Clinic- Minnesota

Rochester, Minnesota, United States, 55905

United States, New York

Memorial Sloan-Kettering Cancer Center

New York, New York, United States, 10065

United States, Pennsylvania

Hospital of the University of Pennsylvania

Philadelphia, Pennsylvania, United States, 19104

United States, Tennessee

Vanderbilt University Medical Center

Nashville, Tennessee, United States, 37232

Sponsors and Collaborators

Tufts Medical Center

Investigators

• Study Chair: Raymond Comenzo, MD; Tufts Medical Center

  Study Documents (Full-Text)

Documents provided by Tufts Medical Center:

Study Protocol and Statistical Analysis Plan  [PDF] July 13, 2017

More Information

• Responsible Party: Tufts Medical Center
• ClinicalTrials.gov Identifier: NCT03168906
• Other Study ID Numbers: NEOD001-RAIN
• First Posted: May 30, 2017
• Results First Posted: December 24, 2019
• Last Update Posted: September 9, 2020
• Last Verified: August 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Tufts Medical Center:

Amyloidosis; NEOD001; RAIN

Additional relevant MeSH terms:

Amyloidosis; Proteostasis Deficiencies; Metabolic Diseases