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Trial record 66 of 119 for:    ZIRCONIUM

Biodistribution of 89Zirconium-labelled GSK2398852 Using PET Imaging

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ClinicalTrials.gov Identifier: NCT03417830
Recruitment Status : Terminated (Change in benefit/risk profile.)
First Posted : January 31, 2018
Results First Posted : August 29, 2019
Last Update Posted : August 29, 2019
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Brief Summary:
The principal aim of this study is to investigate the cardiac uptake of 89Zr-GSK2398852 in subjects with transthyretin cardiomyopathy amyloidosis (ATTR-CM), and its biodistribution to other organs. Low doses of GSK2398852 will be co-administered at levels not high enough for therapeutic benefit. This study will be conducted in two parts: Part A and Part B. Subjects in Part A will participate in up to two dosing sessions and subjects in Part B will participate in one dosing session. Subjects will undergo up to 3 PET scans at varying intervals after 89Zr-GSK2398852 administration. The total duration of study will be approximately 3 to 4 months for subjects in Part A and approximately 2 months for subjects in Part B. Part B of the study will be triggered based on data obtained in Part A and other emerging data.

Condition or disease Intervention/treatment Phase
Amyloidosis Drug: GSK2315698 (CPHPC) Drug: GSK2398852 (unlabeled anti-SAP mAb) Drug: 89Zr-GSK2398852 (89Zr-labeled anti-SAP mAb) Phase 1

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 2 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: Part A of the study will include 3 subjects with ATTR-CM who will participate in two dosing sessions and Part B of the study will include 3 subjects with ATTR-CM who will participate in one dosing session. A single dosing session will constitute treatment with carboxy pyrrolidine hexanoyl pyrrolidine carboxylate (CPHPC), total mass dose (TMD) administration of anti-serum amyloid P (SAP) monoclonal antibody (mAb) consisting of in vivo mixing of a single infusion of unlabeled anti-SAP mAb and a separate infusion of 89Zr-GSK2398852 via a different peripheral venous line, and up to 3 serial PET scanning procedures after administration of 89Zr-GSK2398852.
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: An Adaptive, Open-Label Study to Evaluate the Biodistribution of 89Zirconium-labelled GSK2398852 in the Heart and Other Organs of Patients With Transthyretin Cardiomyopathy (ATTR-CM) Using Positron Emission Tomography (PET) Imaging
Actual Study Start Date : April 6, 2018
Actual Primary Completion Date : July 20, 2018
Actual Study Completion Date : July 20, 2018

Resource links provided by the National Library of Medicine

Drug Information available for: Zirconium

Arm Intervention/treatment
Experimental: Subjects with ATTR-CM in Part A
Approximately 3 subjects with either wild type or inherited ATTR-CM will be included. Subjects in Part A will participate in two anti-SAP dosing sessions approximately 26 days in duration. The first two subjects in Part A will have up to three 89Zr PET scans, while the remaining subject will undergo up to two 89Zr PET scans.
Drug: GSK2315698 (CPHPC)
GSK2315698 will be administered as 20 milligrams per hour (20 mg/hour) IV infusion (in the vein) for up to 72 hours followed by 60 milligrams (mg) three times daily as SC injection for 8 days. Dose level and frequency will be adjusted according to renal function.
Other Name: miridesap

Drug: GSK2398852 (unlabeled anti-SAP mAb)
Subjects will be administered up to 490 mg of GSK2398852, IV. Dose level will be adjusted based on emerging imaging data.
Other Name: dezamizumab

Drug: 89Zr-GSK2398852 (89Zr-labeled anti-SAP mAb)
89Zr-GSK2398852 will be available as solution containing 10 mg 89Zr-GSK2398852 for Infusion. Subjects will be administered 37 (Megabecquerel) MBq radioactive dose of 89Zr-GSK2398852 by the IV route at each dosing session.

Experimental: Subjects with ATTR-CM in Part B
Approximately 3 subjects with either wild type or inherited ATTR-CM will be included. Subjects in Part B will participate in one anti-SAP dosing session. Subjects will undergo up to two 89Zr PET scans.
Drug: GSK2315698 (CPHPC)
GSK2315698 will be administered as 20 milligrams per hour (20 mg/hour) IV infusion (in the vein) for up to 72 hours followed by 60 milligrams (mg) three times daily as SC injection for 8 days. Dose level and frequency will be adjusted according to renal function.
Other Name: miridesap

Drug: GSK2398852 (unlabeled anti-SAP mAb)
Subjects will be administered up to 490 mg of GSK2398852, IV. Dose level will be adjusted based on emerging imaging data.
Other Name: dezamizumab

Drug: 89Zr-GSK2398852 (89Zr-labeled anti-SAP mAb)
89Zr-GSK2398852 will be available as solution containing 10 mg 89Zr-GSK2398852 for Infusion. Subjects will be administered 37 (Megabecquerel) MBq radioactive dose of 89Zr-GSK2398852 by the IV route at each dosing session.




Primary Outcome Measures :
  1. Part A- Session 1: Peak Standardized Uptake Values (SUV) in Focal Anatomical Regions of the Heart Following 80-200 mg Dose of Anti-SAP mAb [ Time Frame: Session 1: Days 4, 5, 6 and 8 ]
    SUV was measured radioactivity concentration corrected for radioactive decay and normalized for administered amount of radioactivity per body weight. SUV was analyzed for each region of interest such as blood pool left atrium, blood pool left ventricle, blood pool right ventricle, left ventricle wall - high uptake, left ventricle wall - low uptake, mid septum - high uptake and mid septum - low uptake. Peak SUV values derived from PET images has been presented. All treated population consisted of all participants who received at least one Anti-SAP treatment including 89Zr-GSK2398852.

  2. Part A- Session 2: Peak SUV in Focal Anatomical Regions of the Heart Following Anti-SAP mAb Dose Between 200 mg and <=500 mg [ Time Frame: Session 2: Days 3, 4 and 5 ]
    SUV was measured radioactivity concentration corrected for radioactive decay and normalized for administered amount of radioactivity per body weight. SUV was analyzed for each region of interest such as blood pool left atrium, blood pool left ventricle, blood pool right ventricle, left ventricle wall - high uptake, left ventricle wall - low uptake, mid septum - high uptake and mid septum - low uptake. Peak SUV values derived from PET images has been presented.

  3. Part B: Peak SUV in Focal Anatomical Regions of the Heart Following 80-200 mg Dose of Anti-SAP mAb [ Time Frame: Days 3, 4 and 6 ]
    SUV in focal anatomical regions of the heart was planned to be measured.

  4. Part B: Peak SUV in Focal Anatomical Regions of the Heart Following Anti-SAP mAb Dose Between 200 mg and <=500 mg [ Time Frame: Days 3, 4 and 6 ]
    SUV in focal anatomical regions of the heart was planned to be measured.

  5. Part A- Session 1: Mean SUV of Whole Heart Following 80-200 mg Dose of Anti-SAP mAb [ Time Frame: Session 1: Days 4, 5, 6 and 8 ]
    SUV was measured radioactivity concentration corrected for radioactive decay and normalized for administered amount of radioactivity per body weight.

  6. Part A- Session 2: Mean SUV of Whole Heart Following Anti-SAP mAb Dose Between 200 mg and <=500 mg [ Time Frame: Session 2: Days 3, 4 and 5 ]
    SUV was measured radioactivity concentration corrected for radioactive decay and normalized for administered amount of radioactivity per body weight.

  7. Part B: Mean SUV of Whole Heart Following 80-200 mg Dose of Anti-SAP mAb [ Time Frame: Days 3, 4 and 6 ]
    SUV of whole heart was planned to be measured.

  8. Part B: Mean SUV of Whole Heart Following Anti-SAP mAb Dose Between 200 mg and <=500 mg [ Time Frame: Days 3, 4 and 6 ]
    SUV of whole heart was planned to be measured.


Secondary Outcome Measures :
  1. Part A- Session 1: Mean SUV of Focal Radioactivity Uptake After 80-200 mg Dose of Anti-SAP mAb [ Time Frame: Session 1: Days 4, 5, 6 and 8 ]
    SUV was measured radioactivity concentration corrected for radioactive decay and normalized for administered amount of radioactivity per body weight. SUV was analyzed for each region of interest such as abdominal skin and skin of the back. Mean SUV derived from PET images has been presented.

  2. Part A- Session 1: Mean SUV of Focal Radioactivity Uptake After 80-200 mg Dose of Anti-SAP mAb: Thyriod Gland-goitre Hotspot [ Time Frame: Session 1: Days 4 and 6 ]
    SUV was measured radioactivity concentration corrected for radioactive decay and normalized for administered amount of radioactivity per body weight. SUV was analyzed for thyroid gland-goitre hotspot. Mean SUV derived from PET images has been presented.

  3. Part A- Session 2: Mean SUV of Focal Radioactivity Uptake After Anti-SAP mAb Dose Between 200 mg and <=500 mg [ Time Frame: Session 2: Days 3, 4 and 5 ]
    SUV was measured radioactivity concentration corrected for radioactive decay and normalized for administered amount of radioactivity per body weight. SUV was analyzed for each region of interest such as thyroid gland-goitre hotspot, abdominal skin and skin of the back. Mean SUV derived from PET images has been presented.

  4. Part B: Mean SUV of Focal Radioactivity Uptake After 80-200 mg Dose of Anti-SAP mAb [ Time Frame: Days 3, 4 and 6 ]
    SUV of focal radioactivity uptake for different organs/tissues was planned to be measured.

  5. Part B: Mean SUV of Focal Radioactivity Uptake After Anti-SAP mAb Dose Between 200 mg and <=500 mg [ Time Frame: Days 3, 4 and 6 ]
    SUV of focal radioactivity uptake for different organs/tissues was planned to be measured.

  6. Part A- Session 1: Mean SUV of Total Radioactivity Uptake After 80-200 mg Dose of Anti-SAP mAb [ Time Frame: Session 1: Days 4, 5, 6 and 8 ]
    SUV was measured radioactivity concentration corrected for radioactive decay and normalized for administered amount of radioactivity per body weight. SUV was analyzed for each region of interest such as adrenal gland, aorta, bone marrow, kidney, liver, spleen, abdominal region, brain, lung, parotid gland, and thigh. Mean SUV derived from PET images has been presented.

  7. Part A- Session 1: Mean SUV of Total Radioactivity Uptake After 80-200 mg Dose of Anti-SAP mAb: Thyroid Gland-goitre [ Time Frame: Session 1: Days 4 and 6 ]
    SUV was measured radioactivity concentration corrected for radioactive decay and normalized for administered amount of radioactivity per body weight. SUV was analyzed for thyroid gland-goitre. Mean SUV derived from PET images has been presented.

  8. Part A- Session 1: Mean SUV of Total Radioactivity Uptake After 80-200 mg Dose of Anti-SAP mAb: Testes [ Time Frame: Session 1: Days 4, 5 and 8 ]
    SUV was measured radioactivity concentration corrected for radioactive decay and normalized for administered amount of radioactivity per body weight. SUV was analyzed for testes. Mean SUV derived from PET images has been presented.

  9. Part A- Session 2: Mean SUV of Total Radioactivity Uptake After Anti-SAP mAb Dose Between 200 mg and <=500 mg [ Time Frame: Session 2: Days 3, 4, and 5 ]
    SUV was measured radioactivity concentration corrected for radioactive decay and normalized for administered amount of radioactivity per body weight. SUV was analyzed for each region of interest such as adrenal gland, aorta, bone marrow, kidney, liver, spleen, abdominal region, brain, lung, parotid gland, thigh, and thyroid gland- goitre. Mean SUV derived from PET images has been presented.

  10. Part B: Mean SUV of Total Radioactivity Uptake After 80-200 mg Dose of Anti-SAP mAb [ Time Frame: Days 3, 4 and 6 ]
    SUV of total radioactivity uptake for different organs/tissues was planned to be measured.

  11. Part B: Mean SUV of Total Radioactivity Uptake After an Anti-SAP mAb Dose Between 200 mg and <=500 mg [ Time Frame: Days 3, 4 and 6 ]
    SUV of total radioactivity uptake for different organs/tissues was planned to be measured.

  12. Part A: Maximum Concentration in Plasma (Cmax) of Total mAb [ Time Frame: Sessions 1 and 2: Day 3 (pre-dose, halfway infusion, end of infusion, 4 and 7 hours after end of infusion), Days 4, 5, 6 and 7 ]
    Blood samples were collected at indicated time points for pharmacokinetic (PK) analysis of total mAb (unlabelled GSK2398852 and 89Zr-GSK2398852). PK Population consisted of all participants from the All Treated Population for whom a PK sample was obtained and analyzed.

  13. Part B: Cmax of Total mAb [ Time Frame: Day 3 (pre-dose, end of infusion, 4 and 7 hours post-infusion), Days 4, 5, 6, 7 and 8 ]
    Blood samples were planned to be collected at indicated time points for PK analysis of total mAb.

  14. Part A: Time Associated With Cmax (Tmax) of Total mAb [ Time Frame: Sessions 1 and 2: Day 3 (pre-dose, halfway infusion, end of infusion, 4 and 7 hours after end of infusion), Days 4, 5, 6 and 7 ]
    Blood samples were collected at indicated time points for PK analysis of total mAb (unlabelled GSK2398852 and 89Zr-GSK2398852).

  15. Part B: Tmax of Total mAb [ Time Frame: Day 3 (pre-dose, end of infusion, 4 and 7 hours post-infusion), Days 4, 5, 6, 7 and 8 ]
    Blood samples were planned to be collected at indicated time points for PK analysis of total mAb.

  16. Part A: Clearance of Total mAb [ Time Frame: Sessions 1 and 2: Day 3 (pre-dose, halfway infusion, end of infusion, 4 and 7 hours after end of infusion), Days 4, 5, 6 and 7 ]
    Blood samples were collected at indicated time points for PK analysis of total mAb (unlabelled GSK2398852 and 89Zr-GSK2398852).

  17. Part B: Clearance of Total mAb [ Time Frame: Day 3 (pre-dose, end of infusion, 4 and 7 hours post-infusion), Days 4, 5, 6, 7 and 8 ]
    Blood samples were planned to be collected at indicated time points for PK analysis of total mAb.

  18. Part A: Terminal Half-life (T1/2) of Total mAb [ Time Frame: Sessions 1 and 2: Day 3 (pre-dose, halfway infusion, end of infusion, 4 and 7 hours after end of infusion), Days 4, 5, 6 and 7 ]
    Blood samples were collected at indicated time points for PK analysis of total mAb (unlabelled GSK2398852 and 89Zr-GSK2398852).

  19. Part B: T1/2 of Total mAb [ Time Frame: Day 3 (pre-dose, end of infusion, 4 and 7 hours post-infusion), Days 4, 5, 6, 7 and 8 ]
    Blood samples were planned to be collected at indicated time points for PK analysis of total mAb.

  20. Part A:Area Under the Concentration Time Curve Till Last Observation (AUC[0 to t]) of Total mAb [ Time Frame: Sessions 1 and 2: Day 3 (pre-dose, halfway infusion, end of infusion, 4 and 7 hours after end of infusion), Days 4, 5, 6 and 7 ]
    Blood samples were collected at indicated time points for PK analysis of total mAb (unlabelled GSK2398852 and 89Zr-GSK2398852).

  21. Part B: AUC(0 to t) of Total mAb [ Time Frame: Day 3 (pre-dose, end of infusion, 4 and 7 hours post-infusion), Days 4, 5, 6, 7 and 8 ]
    Blood samples were planned to be collected at indicated time points for PK analysis of total mAb.

  22. Part A: Area Under the Concentration Time Curve Till Time Infinity (AUC[0 to Infinity]) of Total mAb [ Time Frame: Sessions 1 and 2: Day 3 (pre-dose, halfway infusion, end of infusion, 4 and 7 hours after end of infusion), Days 4, 5, 6 and 7 ]
    Blood samples were collected at indicated time points for PK analysis of total mAb (unlabelled GSK2398852 and 89Zr-GSK2398852).

  23. Part B: AUC(0 to Infinity) of Total mAb [ Time Frame: Day 3 (pre-dose, end of infusion, 4 and 7 hours post-infusion), Days 4, 5, 6, 7 and 8 ]
    Blood samples were planned to be collected at indicated time points for PK analysis of total mAb.

  24. Part A: Cmax of 89Zr-GSK2398852 PKs of Radioactivity (Radio-PK) [ Time Frame: Sessions 1 and 2: Day 3 (10 minutes, 60 minutes, 4 hours, 7 hours post-dose), Days 4, 5 and 6 ]
    Blood samples were collected at indicated time points for measurement of radioactivity. Radioactivity reflected the total concentration of 89Zr-GSK2398852 and its radioactive metabolites. Plasma radioactive concentration was measured using scintillation counter.

  25. Part B: Cmax of 89Zr-GSK2398852 Radio-PK [ Time Frame: Day 3 (10 minutes, 60 minutes, 4 hours, 7 hours post-dose), Days 4, 5 and 6 ]
    Blood samples were planned to be collected at indicated time points for measurement of radioactivity. Radioactivity reflected the total concentration of 89Zr-GSK2398852 and its radioactive metabolites. Plasma radioactive concentration was planned to be measured by scintillation counter.

  26. Part A: Tmax of 89Zr- GSK2398852 Radio-PK [ Time Frame: Sessions 1 and 2: Day 3 (10 minutes, 60 minutes, 4 hours, 7 hours post-dose), Days 4, 5 and 6 ]
    Blood samples were collected at indicated time points for measurement of radioactivity. Radioactivity reflected the total concentration of 89Zr-GSK2398852 and its radioactive metabolites. Plasma radioactive concentration was measured using scintillation counter.

  27. Part B: Tmax of 89Zr-GSK2398852 Radio-PK [ Time Frame: Day 3 (10 minutes, 60 minutes, 4 hours, 7 hours post-dose), Days 4, 5 and 6 ]
    Blood samples were planned to be collected at indicated time points for measurement of radioactivity. Radioactivity reflected the total concentration of 89Zr-GSK2398852 and its radioactive metabolites. Plasma radioactive concentration was planned to be measured by scintillation counter.

  28. Part A: T1/2 of 89Zr- GSK2398852 Radio-PK [ Time Frame: Sessions 1 and 2: Day 3 (10 minutes, 60 minutes, 4 hours, 7 hours post-dose), Days 4, 5 and 6 ]
    Blood samples were collected at indicated time points for measurement of radioactivity. Radioactivity reflected the total concentration of 89Zr-GSK2398852 and its radioactive metabolites. Plasma radioactive concentration was measured using scintillation counter.

  29. Part B: T1/2 of 89Zr- GSK2398852 Radio-PK [ Time Frame: Day 3 (10 minutes, 60 minutes, 4 hours, 7 hours post-dose), Days 4, 5 and 6 ]
    Blood samples were planned to be collected at indicated time points for measurement of radioactivity. Radioactivity reflected the total concentration of 89Zr-GSK2398852 and its radioactive metabolites. Plasma radioactive concentration was planned to be measured by scintillation counter.

  30. Part A: AUC(0 to t) of 89Zr- GSK2398852 Radio-PK [ Time Frame: Sessions 1 and 2: Day 3 (10 minutes, 60 minutes, 4 hours, 7 hours post-dose), Days 4, 5 and 6 ]
    Blood samples were collected at indicated time points for measurement of radioactivity. Radioactivity reflected the total concentration of 89Zr-GSK2398852 and its radioactive metabolites. Plasma radioactive concentration was measured using scintillation counter.

  31. Part B: AUC(0 to t) of 89Zr- GSK2398852 Radio-PK [ Time Frame: Day 3 (10 minutes, 60 minutes, 4 hours, 7 hours post-dose), Days 4, 5 and 6 ]
    Blood samples were planned to be collected at indicated time points for measurement of radioactivity. Radioactivity reflected the total concentration of 89Zr-GSK2398852 and its radioactive metabolites. Plasma radioactive concentration was planned to be measured by scintillation counter.

  32. Part A: AUC(0 to Infinity) of 89Zr- GSK2398852 Radio-PK [ Time Frame: Sessions 1 and 2: Day 3 (10 minutes, 60 minutes, 4 hours, 7 hours post-dose), Days 4, 5 and 6 ]
    Blood samples were collected at indicated time points for measurement of radioactivity. Radioactivity reflected the total concentration of 89Zr-GSK2398852 and its radioactive metabolites. Plasma radioactive concentration was measured using scintillation counter.

  33. Part B: AUC(0 to Infinity) of 89Zr- GSK2398852 Radio-PK [ Time Frame: Day 3 (10 minutes, 60 minutes, 4 hours, 7 hours post-dose), Days 4, 5 and 6 ]
    Blood samples were planned to be collected at indicated time points for measurement of radioactivity. Radioactivity reflected the total concentration of 89Zr-GSK2398852 and its radioactive metabolites. Plasma radioactive concentration was planned to be measured by scintillation counter.

  34. Part A: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to Day 26 of the last session ]
    An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. An SAE is defined as any untoward medical occurrence that, at any dose: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent disability/incapacity; is a congenital anomaly/birth defect; other important medical events which may require medical or surgical intervention. Safety Population consisted of all participants who received at least one dose of GSK2315698, GSK2398852 or 89Zr-GSK2398852.

  35. Part B: Number of Participants With AEs and SAEs [ Time Frame: Up to Day 26 ]
    An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. An SAE is defined as any untoward medical occurrence that, at any dose: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent disability/incapacity; is a congenital anomaly/birth defect; other important medical events which may require medical or surgical intervention.

  36. Part A: Number of Participants With Skin Rashes [ Time Frame: Up to Day 26 of the last session ]
    Rash was graded as Grade 1 to Grade 4 based on symptoms and body surface area (BSA) affected; Grade 1: <10 percent (%) BSA and asymptomatic; Grade 2: 10-30% BSA and/or mild symptoms (pain, itch and burning); Grade 3: >30% BSA and/or moderate/severe symptoms (pain, itch and burning); and Grade 4: any rash with mucosal or systemic involvement (such as evidence of renal involvement).

  37. Part B: Number of Participants With Skin Rashes [ Time Frame: Up to Day 26 ]
    Rash was planned to be graded as Grade 1 to Grade 4 based on symptoms and BSA affected; Grade 1: <10% BSA and asymptomatic; Grade 2: 10-30% BSA and/or mild symptoms (pain, itch and burning); Grade 3: >30% BSA and/or moderate/severe symptoms (pain, itch and burning); and Grade 4: any rash with mucosal or systemic involvement (such as evidence of renal involvement).

  38. Part A: Number of Participants With Cardiac Adverse Events [ Time Frame: Up to Day 26 of the last session ]
    The number of participants with any cardiovascular AEs i.e. any AE coded to the cardiovascular system organ class are presented.

  39. Part B: Number of Participants With Cardiac Adverse Events [ Time Frame: Up to Day 26 ]
    The number of participants with any cardiovascular AEs i.e. any AE coded to the cardiovascular system organ class were planned to be reported.

  40. Part A: Number of Participants With Infusion Related Reactions [ Time Frame: Up to Day 26 of the last session ]
    Number of participants with any infusion related reactions are presented.

  41. Part B: Number of Participants With Infusion Related Reactions [ Time Frame: Up to Day 26 ]
    Number of participants with any infusion related reactions were planned to be reported.

  42. Part A: Change From Baseline in Cardiac Troponin T and N-terminal Prohormone of Brain Natriuretic Peptide (NT-ProBNP) [ Time Frame: Session 1: Baseline (Day 1 Pre-dose), Days 2, 3, 4, 5, 6, 7, 8, 9, 10 and 26; Session 2: Day 1- Pre-dose, Days 2, 3, 4, 5, 6, 7, 8, 9, 10 and 26 ]
    Blood samples were collected to analyze the troponin T and NT-ProBNP at indicated time points. Baseline was considered as the latest assessment prior to first administration of either study drug, i.e. GSK2315698 or anti-SAP mAb (labelled or unlabelled) (Day 1, Pre-dose). Change from Baseline was calculated as post-Baseline value minus Baseline value.

  43. Part B: Change From Baseline in Cardiac Troponin T and NT-ProBNP [ Time Frame: Baseline and up to Day 26 ]
    Blood samples were planned to be collected to analyze the troponin T and NT-ProBNP at indicated time points. Baseline was considered as the latest pre-dose assessment prior to first administration of either study drug, i.e. GSK2315698 or anti-SAP mAb (labelled or unlabelled) (Day 1, Pre-dose). Change from Baseline was calculated as post-Baseline value minus Baseline value.

  44. Part A: Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Findings [ Time Frame: Up to Day 26 of the last session ]
    12-lead ECGs were measured in a semi-supine position using an automated ECG machine after approximately 5 minutes of rest for the participant. Abnormal findings were categorized as clinically significant (CS) and not clinically significant (NCS). Clinically significant abnormal findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition.

  45. Part B: Number of Participants With Abnormal 12-lead ECG Findings [ Time Frame: Up to Day 26 ]
    12-lead ECGs were planned to be measured in a semi-supine position using an automated ECG machine after approximately 5 minutes of rest for the participant.

  46. Part A: Number of Participants With Abnormal Inpatient Cardiac Telemetry [ Time Frame: Up to Day 26 of the last session ]
    Continuous inpatient cardiac monitoring was performed via remote cardiac telemetry device. Abnormal findings were categorized as CS and NCS. Clinically significant abnormal findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition.

  47. Part B: Number of Participants With Abnormal Inpatient Cardiac Telemetry [ Time Frame: Up to Day 26 ]
    Continuous inpatient cardiac monitoring was planned to be performed via remote cardiac telemetry device.

  48. Part A: Number of Participants With Abnormal Outpatient Cardiac Telemetry [ Time Frame: Up to Day 26 of the last session ]
    Continuous outpatient cardiac monitoring was performed via remote cardiac bodyguardian telemetry device. Abnormal findings were categorized as CS and NCS. Clinically significant abnormal findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition.

  49. Part B: Number of Participants With Abnormal Outpatient Cardiac Telemetry [ Time Frame: Up to Day 26 ]
    Continuous outpatient cardiac monitoring was planned to be performed via remote cardiac bodyguardian telemetry device.

  50. Part A: Number of Participants With Abnormal Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) [ Time Frame: Up to Day 26 of the last session ]
    SBP and DBP were measured in a semi-supine position after 5 minutes of rest for the participant. Potential Clinical Importance (PCI) ranges for the SBP and DBP were as follows: SBP- <90 and >180 millimeters of mercury (mmHg), and DBP- <30 and >110 mmHg.

  51. Part B: Number of Participants With Abnormal SBP and DBP [ Time Frame: Up to Day 26 ]
    SBP and DBP were planned to be measured in a semi-supine position after 5 minutes of rest for the participant.

  52. Part A: Number of Participants With Abnormal Temperature [ Time Frame: Up to Day 26 of the last session ]
    Temperature was measured in a semi-supine position after 5 minutes of rest for the participant. Normal range for temperature was as follows: temperature- >37.5 degree celsius.

  53. Part B: Number of Participants With Abnormal Temperature [ Time Frame: Up to Day 26 ]
    Temperature was planned to be measured in a semi-supine position after 5 minutes of rest for the participant.

  54. Part A: Number of Participants With Abnormal Respiratory Rate [ Time Frame: Up to Day 26 of the last session ]
    Respiratory rate was measured in a semi-supine position after 5 minutes of rest for the participant. Normal range for the respiratory rate was as follows: respiratory rate- <12 and >25 breaths per minute.

  55. Part B: Number of Participants With Abnormal Respiratory Rate [ Time Frame: Up to Day 26 ]
    Respiratory rate was planned to be measured in a semi-supine position after 5 minutes of rest for the participant.

  56. Part A: Number of Participants With Abnormal Pulse Rate [ Time Frame: Up to Day 26 of the last session ]
    Pulse rate were measured in a semi-supine position after 5 minutes of rest for the participant. PCI range for the pulse rate was as follows: pulse rate- <35 and >140 beats per minute (bpm).

  57. Part B: Number of Participants With Abnormal Pulse Rate [ Time Frame: Up to Day 26 ]
    Pulse rate was planned to be measured in a semi-supine position after 5 minutes of rest for the participant.

  58. Part A: Number of Participants With New Abnormal Physical Examination Findings [ Time Frame: Session 1: At screening (within 35 days of Anti-SAP treatment of session 1), Day 1 Pre-dose, Day 3, Day 5, Day 8 and Day 11; Session 2: Day 1 Pre-dose, Day 3, Day 5, Day 8 and Day 11 ]
    A full and brief physical examination was performed, including assessments of the skin, lungs, cardiovascular system and abdomen (liver and spleen).

  59. Part B: Number of Participants With New Abnormal Physical Examination Findings [ Time Frame: At screening (within 35 days of Anti-SAP treatment), Days 1, 3, 5, 8 and 11 ]
    A full and brief physical examination was planned to be performed, including assessments of the skin, lungs, cardiovascular system and abdomen (liver and spleen).

  60. Part A: Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelets [ Time Frame: Session 1: Baseline (Day 1 Pre-dose), Days 3, 5, 7, 10 and 26; Session 2: Day 1-Pre-dose, Days 3, 5, 7, 10 and 26 ]
    Blood samples were collected to analyze the hematology parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils and Platelets. Baseline was considered as the latest pre-dose assessment prior to first administration of either study drug, i.e. GSK2315698 or anti-SAP mAb (labelled or unlabelled) (Day 1, Pre-dose). Change from Baseline was calculated as post-Baseline value minus Baseline value.

  61. Part B: Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelets [ Time Frame: Baseline (Day 1 Pre-dose), Days 3, 5, 7, 10 and 26 ]
    Blood samples were planned to be collected to analyze the hematology parameters.

  62. Part A: Change From Baseline in Hematology Parameter: Hematocrit [ Time Frame: Session 1: Baseline (Day 1 Pre-dose), Days 3, 5, 7, 10 and 26; Session 2: Day 1-Pre-dose, Days 3, 5, 7, 10 and 26 ]
    Blood samples were collected to analyze the hematology parameter: Hematocrit. Baseline was considered as the latest pre-dose assessment prior to first administration of either study drug, i.e. GSK2315698 or anti-SAP mAb (labelled or unlabelled) (Day 1, Pre-dose). Change from Baseline was calculated as post-Baseline value minus Baseline value.

  63. Part B: Change From Baseline in Hematology Parameter: Hematocrit [ Time Frame: Baseline (Day 1 Pre-dose), Days 3, 5, 7, 10 and 26 ]
    Blood samples were planned to be collected to analyze the hematology parameter.

  64. Part A: Change From Baseline in Hematology Parameter: Hemoglobin [ Time Frame: Session 1: Baseline (Day 1 Pre-dose), Days 3, 5, 7, 10 and 26; Session 2: Day 1- Pre-dose, Days 3, 5, 7, 10 and 26 ]
    Blood samples were collected to analyze the hematology parameter: Hemoglobin. Baseline was considered as the latest pre-dose assessment prior to first administration of either study drug, i.e. GSK2315698 or anti-SAP mAb (labelled or unlabelled) (Day 1, Pre-dose). Change from Baseline was calculated as post-Baseline value minus Baseline value.

  65. Part B: Change From Baseline in Hematology Parameter: Hemoglobin [ Time Frame: Baseline (Day 1 Pre-dose), Days 3, 5, 7, 10 and 26 ]
    Blood samples were planned to be collected to analyze the hematology parameter.

  66. Part A: Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Hemoglobin [ Time Frame: Session 1: Baseline (Day 1 Pre-dose), Days 3, 5, 7, 10 and 26; Session 2: Day 1- Pre-dose, Days 3, 5, 7, 10 and 26 ]
    Blood samples were collected to analyze the hematology parameter: Erythrocytes Mean Corpuscular Hemoglobin. Baseline was considered as the latest pre-dose assessment prior to first administration of either study drug, i.e. GSK2315698 or anti-SAP mAb (labelled or unlabelled) (Day 1, Pre-dose). Change from Baseline was calculated as post-Baseline value minus Baseline value.

  67. Part B: Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Hemoglobin [ Time Frame: Baseline (Day 1 Pre-dose), Days 3, 5, 7, 10 and 26 ]
    Blood samples were planned to be collected to analyze the hematology parameter.

  68. Part A: Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Volume [ Time Frame: Session 1: Baseline (Day 1 Pre-dose), Days 3, 5, 7, 10 and 26; Session 2: Day 1- Pre-dose, Days 3, 5, 7, 10 and 26 ]
    Blood samples were collected to analyze the hematology parameter: Erythrocytes Mean Corpuscular Volume. Baseline was considered as the latest pre-dose assessment prior to first administration of either study drug, i.e. GSK2315698 or anti-SAP mAb (labelled or unlabelled) (Day 1, Pre-dose). Change from Baseline was calculated as post-Baseline value minus Baseline value.

  69. Part B: Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Volume [ Time Frame: Baseline (Day 1 Pre-dose), Days 3, 5, 7, 10 and 26 ]
    Blood samples were planned to be collected to analyze the hematology parameter.

  70. Part A: Change From Baseline in Hematology Parameters: Erythrocytes, Reticulocytes [ Time Frame: Session 1: Baseline (Day 1 Pre-dose), Days 3, 5, 7, 10 and 26; Session 2: Day 1- Pre-dose, Days 3, 5, 7, 10 and 26 ]
    Blood samples were collected to analyze the hematology parameters: Erythrocytes and Reticulocytes. Baseline was considered as the latest pre-dose assessment prior to first administration of either study drug, i.e. GSK2315698 or anti-SAP mAb (labelled or unlabelled) (Day 1, Pre-dose). Change from Baseline was calculated as post-Baseline value minus Baseline value.

  71. Part B: Change From Baseline in Hematology Parameters: Erythrocytes, Reticulocytes [ Time Frame: Baseline (Day 1 Pre-dose), Days 3, 5, 7, 10 and 26 ]
    Blood samples were planned to be collected to analyze the hematology parameters.

  72. Part A: Change From Baseline in Chemistry Parameters: Glucose, Calcium, Potassium, Sodium, Urea [ Time Frame: Session 1: Baseline (Day 1 Pre-dose), Days 3, 5, 7, 10 and 26; Session 2: Day 1- Pre-dose, Days 3, 5, 7, 10 and 26 ]
    Blood samples were collected to analyze the chemistry parameters: Glucose, Calcium, Potassium, Sodium and Urea. Baseline was considered as the latest pre-dose assessment prior to first administration of either study drug, i.e. GSK2315698 or anti-SAP mAb (labelled or unlabelled) (Day 1, Pre-dose). Change from Baseline was calculated as post-Baseline value minus Baseline value.

  73. Part B: Change From Baseline in Chemistry Parameters: Glucose, Calcium, Potassium, Sodium, Urea [ Time Frame: Baseline (Day 1 Pre-dose), Days 3, 5, 7, 10 and 26 ]
    Blood samples were planned to be collected to analyze the chemistry parameters.

  74. Part A: Change From Baseline in Chemistry Parameters: Albumin, Protein [ Time Frame: Session 1: Baseline (Day 1 Pre-dose), Days 3, 5, 7, 10 and 26; Session 2: Day 1- Pre-dose, Days 3, 5, 7, 10 and 26 ]
    Blood samples were collected to analyze the chemistry parameters: Albumin and Protein. Baseline was considered as the latest pre-dose assessment prior to first administration of either study drug, i.e. GSK2315698 or anti-SAP mAb (labelled or unlabelled) (Day 1, Pre-dose). Change from Baseline was calculated as post-Baseline value minus Baseline value.

  75. Part B: Change From Baseline in Chemistry Parameters: Albumin, Protein [ Time Frame: Baseline (Day 1 Pre-dose), Days 3, 5, 7, 10 and 26 ]
    Blood samples were planned to be collected to analyze the chemistry parameters.

  76. Part A: Change From Baseline in Chemistry Parameters: Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) [ Time Frame: Session 1: Baseline (Day 1 Pre-dose), Days 3, 5, 7, 10 and 26; Session 2: Day 1- Pre-dose, Days 3, 5, 7, 10 and 26 ]
    Blood samples were collected to analyze the chemistry parameters: ALP, ALT and AST. Baseline was considered as the latest pre-dose assessment prior to first administration of either study drug, i.e. GSK2315698 or anti-SAP mAb (labelled or unlabelled) (Day 1, Pre-dose). Change from Baseline was calculated as post-Baseline value minus Baseline value.

  77. Part B: Change From Baseline in Chemistry Parameters: ALP, ALT, AST [ Time Frame: Baseline (Day 1 Pre-dose), Days 3, 5, 7, 10 and 26 ]
    Blood samples were planned to be collected to analyze the chemistry parameters.

  78. Part A: Change From Baseline in Chemistry Parameters: Direct Bilirubin, Bilirubin, Creatinine [ Time Frame: Session 1: Baseline (Day 1 Pre-dose), Days 3, 5, 7, 10 and 26; Session 2: Day 1- Pre-dose, Days 3, 5, 7, 10 and 26 ]
    Blood samples were collected to analyze the chemistry parameters: Direct Bilirubin, Bilirubin, Creatinine. Baseline was considered as the latest pre-dose assessment prior to first administration of either study drug, i.e. GSK2315698 or anti-SAP mAb (labelled or unlabelled) (Day 1, Pre-dose). Change from Baseline was calculated as post-Baseline value minus Baseline value.

  79. Part B: Change From Baseline in Chemistry Parameters: Direct Bilirubin, Bilirubin, Creatinine [ Time Frame: Baseline (Day 1 Pre-dose), Days 3, 5, 7, 10 and 26 ]
    Blood samples were planned to be collected to analyze the chemistry parameters.

  80. Part A: Number of Participants With Abnormal Urinalysis Parameters: Glucose, Protein, Blood, Ketones [ Time Frame: Up to Day 26 of the last session ]
    Urine samples were collected to analyze urinalysis parameters including glucose, protein, blood and ketones.

  81. Part A: Number of Participants With Abnormal Urinalysis Parameters: Specific Gravity, Potential of Hydrogen [ Time Frame: Up to Day 26 of the last session ]
    Urine samples were collected to analyze urinalysis parameters including specific gravity and potential of hydrogen.

  82. Part B: Number of Participants With Abnormal Urinalysis Parameters: Glucose, Protein, Blood, Ketones [ Time Frame: Up to Day 26 ]
    Urine samples were planned to be collected to analyze the urinalysis parameters.

  83. Part B: Number of Participants With Abnormal Urinalysis Parameters: Specific Gravity, Potential of Hydrogen [ Time Frame: Up to Day 26 ]
    Urine samples were planned to be collected to analyze the urinalysis parameters.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   65 Years to 80 Years   (Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Subject must be 65 to 80 years of age inclusive, at the time of signing the informed consent.
  • Subjects with a diagnosis of ATTR-CM: a) Wild-type ATTR status must be confirmed by genotyping and have one of the following: i) Definite histochemical identification of amyloid by Congo red staining and green birefringence in crossed polarized light in cardiac or other tissue biopsy and identification of Transthyretin amyloidosis (TTR) as the amyloid fibril protein either by immunohistochemistry or proteomic analysis OR ii) Scintigraphy Technetium-99m-labeled 3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) with confirmed myocardial uptake. b) Hereditary ATTR amyloidosis (example, TTR Val30Met) should have a known amyloidogenic TTR mutation demonstrated by genotyping and is recognized to be primarily associated with cardiomyopathy and one of the following: i) Definite histochemical identification of amyloid by Congo red staining and green birefringence in crossed polarized light in cardiac or other tissue biopsy and identification of TTR as the amyloid fibril protein either by immunohistochemistry or proteomic analysis. ii) Scintigraphy: 99mTc-DPD with confirmed myocardial uptake.
  • Both male and female subjects are eligible to participate. a) Male subjects: A male subject must agree to use contraception during the treatment period and for at least 3 months after the last scan and refrain from donating sperm during this period. b) Female subjects: A female subject is eligible to participate if she is not of childbearing potential.
  • Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and protocol.
  • New York Heart Association (NYHA) up to class 3; subjects should be clinically stable for at least 3 months preceding to Screening.

Exclusion Criteria:

  • Cardiomyopathy primarily caused by non-amyloid diseases (example, ischemic heart disease; valvular heart disease).
  • Interval from the Q wave on the ECG to point T using Fredericia's formula (QTcF) >500 milliseconds (msec).
  • Sustained (at a rate of >=120 beats per minute for >=30 seconds), or symptomatic monomorphic ventricular tachycardia (VT), or rapid polymorphic VT, at Screening/Baseline cardiac monitoring.
  • Systolic blood pressure <=100 millimeters of mercury (mm/Hg) based on triplicate readings at Screening.
  • Unstable heart failure defined as emergency hospitalization for worsening, or decompensated heart failure, or syncopal episode within 1 month of screening.
  • Implantable cardiac defibrillator (ICD) or permanent pacemaker (PPM) at Screening.
  • Estimated Glomerular filtration rate (eGFR) at Screening <50 milliliters per minute (mL/min) calculated using modification of diet in renal disease (MDRD).
  • Any active and persistent dermatological condition, which in the opinion of the Investigator and Medical Monitor would preclude safe participation.
  • History of allogeneic stem cell transplantation, prior solid organ transplant, or anticipated to undergo solid organ transplantation, or left ventricular assist device (LVAD) implantation.
  • Malignancy within last 5 years, except for basal or squamous cell carcinoma of the skin, or carcinoma in situ of the cervix that has been successfully treated.
  • Acute coronary syndrome, or any form of coronary revascularization procedure (including coronary artery bypass grafting [CABG]), within 6 months of screening.
  • Symptomatic, clinically significant autonomic neuropathy which the Principal Investigator (PI) feels will preclude administration of study treatment.
  • Uncontrolled hypertension during Screening.
  • ALT >3 times upper limit of normal (ULN) OR bilirubin >1.5 times ULN (isolated bilirubin >1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
  • Peripheral edema at Screening that in the opinion of the PI or designee might prevent adequate absorption of subcutaneously administered CPHPC.
  • Presence of any co-morbid (example, steroid refractory rheumatoid arthritis), or an uncontrolled medical condition (example, diabetes mellitus), which in the opinion of the investigator would increase the potential risk to the subject. Investigator should liaise with the Medical Monitor where there is uncertainty as to the eligibility of a subject.
  • Positive test for hepatitis B, hepatitis C and/or human immunodeficiency virus (HIV) during Screening, or within 3 months prior to first dose of study treatment.
  • Clinically significant multiple or severe drug allergies, intolerance to topical corticosteroids, or severe post-treatment hypersensitivity reactions (including, but not limited to, erythema multiforme major, linear immunoglobulin A [IgA] dermatosis, toxic epidermal necrolysis and exfoliative dermatitis).
  • Inability to comprehend and/or understand the study patient information sheet, and/or unwillingness or inability to follow the procedures outlined in the protocol.
  • Has any of the following: a) Fulfillment of diagnostic criteria for Amyloid Light-chain (AL) amyloidosis. b) Fulfillment of diagnostic criteria for amyloid A (AA) or non-TTR hereditary amyloidosis.
  • ATTR Disease Load: c) Histologically proven or clinically suspected gastrointestinal TTR amyloidosis; d) Diffuse skeletal muscle uptake of 99m(Tc)-DPD on Single-photon emission computed tomography (SPECT) imaging (where available); e) Peripheral neuropathy causing more than mild morbidity (example, walking disability; neuropathic pain affecting activities of daily living); f) Proven or clinically suspected intracranial TTR involvement including ophthalmological disease.
  • Non-amyloidosis related chronic liver disease (with the exception of Gilbert's syndrome or clinically asymptomatic gallstones).
  • Participation in a separate clinical trial involving CPHPC within 3 months of Screening.
  • Any prohibited concomitant medication within referenced timeframe.
  • Treatment with another investigational drug, biological agent, or device within 6 months of screening, or 5 half-lives of the study agent, whichever is longer.
  • Orthopnea of sufficient severity to preclude supine scanning as determined at Screening.
  • Inability to fit inside scanner due to body size (girth).
  • History of claustrophobia.
  • Contraindication to magnetic resonance imaging (MRI) contrast agents.
  • Contraindication for MRI scanning (as assessed by local MRI safety questionnaire), which includes but is not limited to: a) Intracranial aneurysm clips (except Sugita) or other metallic objects; b) Intra-orbital metal fragments that have not been removed; c) Pacemakers or other implanted cardiac rhythm management/monitoring devices and non-magnetic resonance (MR) conditional heart valves; d) Inner ear implants.
  • Donation of blood or blood products in excess of 500 milliliters (mL) within 84 days of Screening.
  • Poor or unsuitable venous access.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03417830


Locations
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Sweden
GSK Investigational Site
Uppsala, Sweden, SE-751 85
Sponsors and Collaborators
GlaxoSmithKline
Investigators
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Study Director: GSK Clinical Trials GlaxoSmithKline
  Study Documents (Full-Text)

Documents provided by GlaxoSmithKline:
Study Protocol  [PDF] October 4, 2017
Statistical Analysis Plan  [PDF] February 19, 2019


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Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT03417830     History of Changes
Other Study ID Numbers: 204512
2017-002665-22 ( EudraCT Number )
First Posted: January 31, 2018    Key Record Dates
Results First Posted: August 29, 2019
Last Update Posted: August 29, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: IPD for this study will be made available via the Clinical Study Data Request site.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints of the study.
Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.
URL: http://clinicalstudydatarequest.com

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by GlaxoSmithKline:
miridesap
GSK2315698
89Zirconium labelled
Positron Emission Tomography
Transthyretin cardiomyopathy
GSK2398852
dezamizumab
Additional relevant MeSH terms:
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Amyloidosis
Proteostasis Deficiencies
Metabolic Diseases