A Study to Evaluate the Safety of GSK2398852 When Co-administered With GSK2315698 in Patients With Systemic Amyloidosis

NCT ID: NCT01777243

Last Updated: 2018-07-24

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 25 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-05-13
• Study Completion Date: 2015-12-22

Brief Summary

The study will be conducted in two parts. The first (Part A) will be an open label single dose escalation part beginning with the proposed starting dose level of GSK2398852 as 5 milligram (mg) [approximately equivalent to 0.1 mg/kilogram (kg)]. The next escalation dose levels are proposed as 1 mg/kg, 3 mg/kg, 10 mg/kg and 30 mg/kg. GSK2315698 will be administered at variable doses until the concentration of the serum amyloid P component monoclonal antibody (SAP mAb) has fallen below 100 nanogram/millilitre (ng/mL). Decisions about these next dose levels will be made following safety review of the prior subjects' data; dose levels may be changed (increased and lowered) and dose levels may be repeated depending on the observed safety such that Part A extension study may be performed. In addition, pharmacokinetics of GSK2315698 (SAP depleter) and GSK2398852 (anti-SAP mAb), and circulating SAP concentrations will be assessed. Dose escalation in Part A will continue to the highest well tolerated dose or the highest allowable dose. Subjects will be closely monitored and will undergo Equilibrium contrast Magnetic Resonance Imaging (EqMRI) including organ volume, Elastography and Liver Biopsy if required.

Part B will be a randomized partially blinded part with the principal objective of assessing the dose response of the GSK2398852 in more detail. Subjects will be assigned to one of approximately 5 dose groups from Part A. The precise selection of numbers of subjects and dose levels will be informed by the results from Part A.

Conditions

Amyloidosis

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Part A Arm

Two subjects in Part A will receive starting dose level of GSK2398852 as 5 milligram (mg) \[approximately equivalent to 0.1 mg/kilogram (kg)\]. The next escalation dose levels in two subjects each are proposed as 1 mg/kg, 3 mg/kg, 10 mg/kg and 30 mg/kg. GSK2315698 will be administered at variable dosed until the concentration of the SAP mAb has fallen below 100 ng/mL.

Group Type: EXPERIMENTAL

GSK2398852

Intervention Type: DRUG

Unit dose strength: 100 mg/mL provided as 1 mL solution per vial. GSK2398852 dosage levels variable with the proposed starting dose level of GSK2398852 as 5 mg \[approximately equivalent to 0.1 mg/ kg\]. The next escalation dose levels are proposed as 1 mg/kg, 3 mg/kg, 10 mg/kg and 30 mg/kg.

GSK2315698

Intervention Type: DRUG

Unit dose strength: 200 mg/mL stock to be diluted. GSK2315698 will be administered at variable dosed until the concentration of the serum amyloid P component monoclonal antibody (SAP mAb) has fallen below 100 ng/mL.

Part B Arm

The precise selection of numbers of subjects and dose levels in Part B will be informed by the results from Part A.

Group Type: EXPERIMENTAL

GSK2398852

Intervention Type: DRUG

Unit dose strength: 100 mg/mL provided as 1 mL solution per vial. GSK2398852 dosage levels variable with the proposed starting dose level of GSK2398852 as 5 mg \[approximately equivalent to 0.1 mg/ kg\]. The next escalation dose levels are proposed as 1 mg/kg, 3 mg/kg, 10 mg/kg and 30 mg/kg.

GSK2315698

Intervention Type: DRUG

Unit dose strength: 200 mg/mL stock to be diluted. GSK2315698 will be administered at variable dosed until the concentration of the serum amyloid P component monoclonal antibody (SAP mAb) has fallen below 100 ng/mL.

Interventions

GSK2398852

Unit dose strength: 100 mg/mL provided as 1 mL solution per vial. GSK2398852 dosage levels variable with the proposed starting dose level of GSK2398852 as 5 mg \[approximately equivalent to 0.1 mg/ kg\]. The next escalation dose levels are proposed as 1 mg/kg, 3 mg/kg, 10 mg/kg and 30 mg/kg.

Intervention Type: DRUG

GSK2315698

Unit dose strength: 200 mg/mL stock to be diluted. GSK2315698 will be administered at variable dosed until the concentration of the serum amyloid P component monoclonal antibody (SAP mAb) has fallen below 100 ng/mL.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Subject has been medically diagnosed with systemic amyloidosis and falls into one of the patient groups (small to moderate amyloid load involving the spleen for Part A; moderate to large amyloid load involving the spleen (to a moderate/large extent) for Part A (following agreement from external safety committee); moderate to large amyloid load involving the spleen and liver (spleen involved to a moderate/large extent) for Part A extension (if required); and moderate to large amyloid load involving the spleen (and liver in subset of subjects only) for Part B).
• Alanine aminotransferase (ALT) <3x upper limit of normal (ULN) and bilirubin <1.5x ULN (isolated bilirubin >1.5x ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
• Male or female between 18 and 70 years of age inclusive, at the time of signing the informed consent.
• Subject is ambulant and capable of attending for the study visit schedule.
• Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
• A female subject is eligible to participate if she is of non-childbearing potential; or females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the approved contraception methods.
• Male subjects with female partners of child-bearing potential must agree to use one of the approved contraception methods.
• Smokers (<10 /day) are permitted but must be willing to abstain for the duration of residential study sessions

Exclusion Criteria

• A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening
• The subject has participated in a clinical trial and has received an investigational therapeutic product (unlicensed) within the following time period prior to the first dosing day in the current study: 3 months, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer). This timeframe will not apply to short term administration of GSK2315698 in study CPH114527.
• Pregnant females as determined by positive serum or urine human chorionic gonadotropin (hCG) test at screening or prior to dosing.
• Lactating females.
• Estimated glomerular filtration rate (GFR)<30 milliliter (mL)/minute (min) [<60 mL/min for the first 4 subjects to be enrolled]
• Evidence of an active urinary sediment on microscopy as evidenced by the presence of red cell casts
• Decompensated cardiac failure or a recent history of syncope associated with cardiac disease.
• In a subject in whom there is a clinical suspicion of cardiac amyloid, an echocardiogram is consistent with significant cardiac amyloid, whether symptomatic or not.
• Clinically significant anaemia- hemoglobin (Hb) <9 gram (g)/deciliter (dL).
• Use of prohibited medications.
• Poor or unsuitable venous access.
• Subjects with a QT interval corrected using Fridericia's formulas (QTcF) of >480 ms or other electrocardiogram (ECG) abnormalities which, in the opinion of the investigator are clinically significant and may increase safety risk.
• Uncontrolled hypertension with systolic blood pressure (BP) >170 mmHg and /or diastolic >100 mmHg
• Presence of any co-morbid condition (e.g. severe or unstable coronary artery disease; moderate-severe chronic obstructive pulmonary disease) which in the opinion of the investigator would increase the potential risk to the subject.
• Subjects with active vasculitis
• Exclusions from Equilibrium contrast Magnetic Resonance Imaging (EqMRI) scanning [Contraindications to Magnetic Resonance Imaging (MRI) scanning including, but not limited to: Intracranial aneurism clips (except Sugita); History of intra-orbital metal fragments that have not been removed by an MD (as confirmed by orbital X-Ray); Pacemakers and non-MR compatible heart valves; Inner ear implants; History of claustrophobia; estimated GFR <30 mL/min (gadolinium exclusion)]
• Subjects with dementia or a diagnosis of cerebral amyloid angiopathy.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Imperial College London

OTHER

Sponsor Role: collaborator

Heart Hospital

UNKNOWN

Sponsor Role: collaborator

Royal Free Hospital NHS Foundation Trust

OTHER

Sponsor Role: collaborator

Quintiles, Inc.

INDUSTRY

Sponsor Role: collaborator

GlaxoSmithKline

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

GSK Clinical Trials

Role: STUDY_DIRECTOR

GlaxoSmithKline

Locations

GSK Investigational Site

Cambridge, , United Kingdom

GSK Investigational Site

London, , United Kingdom

Countries

United Kingdom

References

Richards D, Millns H, Cookson L, Lukas MA. An observational, non-interventional study for the follow-up of patients with amyloidosis who received miridesap followed by dezamizumab in a phase 1 study. Orphanet J Rare Dis. 2022 Jul 9;17(1):259. doi: 10.1186/s13023-022-02405-7.

Reference Type: DERIVED

PMID: 35810311 (View on PubMed)

Richards DB, Cookson LM, Barton SV, Liefaard L, Lane T, Hutt DF, Ritter JM, Fontana M, Moon JC, Gillmore JD, Wechalekar A, Hawkins PN, Pepys MB. Repeat doses of antibody to serum amyloid P component clear amyloid deposits in patients with systemic amyloidosis. Sci Transl Med. 2018 Jan 3;10(422):eaan3128. doi: 10.1126/scitranslmed.aan3128.

Reference Type: DERIVED

PMID: 29298867 (View on PubMed)

Richards DB, Cookson LM, Berges AC, Barton SV, Lane T, Ritter JM, Fontana M, Moon JC, Pinzani M, Gillmore JD, Hawkins PN, Pepys MB. Therapeutic Clearance of Amyloid by Antibodies to Serum Amyloid P Component. N Engl J Med. 2015 Sep 17;373(12):1106-14. doi: 10.1056/NEJMoa1504942. Epub 2015 Jul 15.

Reference Type: DERIVED

PMID: 26176329 (View on PubMed)

Other Identifiers

115570

Identifier Type: -

Identifier Source: org_study_id