Clinical trial NCT01777243: A Study to Evaluate the Safety of GSK2398852 When Co-administered With GSK2315698 in Patients With Systemic Amyloidosis
Official title: A Single Dose First in Human Study of GSK2398852 Co-Administered With GSK2315698 in Patients With Systemic Amyloidosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Amyloidosis
Keywords: pharmacokinetic
systemic amyloidosis
safety
dose escalation
Carboxy Pyrrolidine Hexanoyl Pyrrolidine Carboxylate (CPHPC)
biomarker
GSK2315698
GSK2398852
SAP
pharmacodynamic
co-administration
intravenous
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
Collaborators: name: Imperial College London
name: Heart Hospital
name: Royal Free Hospital NHS Foundation Trust
name: Quintiles, Inc.
First posted: 2013-01-28
Enrollment: 25
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: Safety of GSK2398852 as assessed by number of subjects with AEs in Part A and in Part B
timeFrame: Continuous throughout the study
measure: Safety of GSK2398852 as assessed by clinical laboratory tests in Part A and in Part B
timeFrame: At scheduled intervals upto Day 42 in each Part.
measure: Safety of GSK2398852 as assessed by vital signs measurements in Part A and in Part B
timeFrame: At scheduled intervals upto Day 42 in each Part.
measure: Safety of GSK2398852 as assessed by ECG readings in Part A and in Part B
timeFrame: At scheduled intervals upto Day 42 in each Part.
measure: PK profile of GSK2315698 and GSK2398852 in Part A and in Part B
timeFrame: In Part A and Part B on Day -2, Day 1 (pre-dose, 1 hour [hr], 2 hr, 3 hr, 4 hr, 8 hr, 12 hr), Day 2, Day 3, Day 4, Day 6, Day 14, Day 21, Day 42
measure: Dose response of single doses of GSK2398852 when co-administered with GSK2315698 in Part B
timeFrame: Baseline, Day 6, Day 14 and Day 42 in Part B.
Secondary outcomes:
measure: SAP concentrations measurement
timeFrame: Baseline, Day -3, Day -2, Day -1, Day 42 in each Part.
measure: Measurement of anti-drug antibodies before and after treatment with GSK2398852
timeFrame: Day 1 pre-dose, Day 21, Day 42 in each Part.
Other outcomes:
Locations:
city: Cambridge
country: United Kingdom
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.