The AMBAR trial: an interim analysis ASFA Annual Meeting May 6, Palm Springs. CA. Antonio Páez, MD Senior Manager, Clinical Operations Grifols

Transcription

1 The AMBAR trial: an interim analysis ASFA Annual Meeting May 6, 206. Palm Springs. CA Antonio Páez, MD Senior Manager, Clinical Operations Grifols

2 A multicenter, randomized, controlled study to evaluate the efficacy and safety of short-term plasma exchange followed by long-term plasmapheresis with infusion of human albumin combined with intravenous immunoglobulin in patients with mild-moderate Alzheimer s disease 2

3 Study summary Disease: Design: Patients: mild-moderate Alzheimer s disease Phase IIb/III, multicenter, randomized, controlled (sham), parallel-group, patient- and rater-blind 364 patients randomized in 4 groups (:::): 3 treatment groups + control group (sham) Treatments: Total Plasma Exchange with Albumin (Albutein ) Low Volume Plasma Exchange with Albumin (Albutein ) or IGIV (Flebogamma DIF ) Participation: maximum 4 months Sites: Endpoint: 40 sites approx. (20 in Spain and 20 in US) Changes from baseline in Cognitive Status + Activities of Daily Living (ADAS-Cog + ADCS-ADL) Other endpoints: Changes in Aβ40 and Aβ42 in plasma and CSF + Brain volume (MRI) + Functional PET scan Results of a previous Ph2 study with 42 patients presented in the ASFA Annual Meeting

4 Main inclusion criteria year-old A diagnosis of AD (NINCDS-ADRDA) and MMSE between 8 and 26 Stable treatment with acetylcholine esterase inhibitors (AChEIs) and/or memantine for the previous 3 months CAT or MRI obtained in the 2 months prior to recruitment showing absence of cerebrovascular disease A stable care taker available that must attend patient study visits 4 4

5 Main exclusion criteria Any contraindication for plasma exchange Hemoglobin < 0 g/dl Plasma creatinine > 2 mg/dl Uncontrolled high blood pressure (SBP 60 and/or DBP 00 mmhg) Myocardial infarction, severe or unstable angina, or heart failure (New York Heart Association Class II, III or IV) in the past 2 months A history of frequent adverse reactions to blood products 5 5

6 Study treatments Total Plasma Exchange (TPE) Processing of plasma volume Replacement fluid: 5% Albumin (Albutein ) Central or peripheral access Once a week for 6 weeks: 6 procedures No IGIV is infused Sham Treatment Simulation of TPE and LVPE Central and peripheral accesses simulated Devices work in a closed-circuit manner Expired blood and colored fluid used to fill devices No fluid interchange between device and patient Low Volume Plasma Exchange (LVPE) Removal of ml of plasma (like a donation) Replacement with 20% Albutein (different doses) Peripheral access Once a month for 2 months: 2 procedures IGIV is infused to replace endogenous IG 6

7 LVPE/month 364 patients F A A A F A A A F A A A FV A20%: 40g F: 20g B TPE/week - Alb5% TPE TPE TPE TPE TPE TPE IV F A A A F A A A F A A A FV A20%: 20g F: 0g A A A A A A A A A A A A FV A20%: 20g B S S S S S S IV S S S S S S S S S S S S FV Control group Sham treatment Months TPE: Total Plasma Exchange F: Flebogamma DIF 5% (IGIV) : AD Biomarkers : Lumbar Puncture : FDG-PET LVPE: Low Volume Plasma Exchange A: Albutein 5% - 20% (Albumin) : Neuropsychological Tests : MRI 7

8 Current and interim status Spain US Total Interim Participating sites End of interim recruitment June 30 th, 205 Active sites Database lock September 9 th, 205 Patients recruited (Apr.) Patients recruited 86 out of 364 (/2 sample approx.) 8

9 Interim general considerations Description of the patients included as of June 30 th, 205. We describe patient characteristics, safety and tolerability, and treatment feasibility. These are not interim results of the study outcomes. All patients presented together (randomization codes not broken). 9 9

10 Patient disposition Recruited patients (n= 86) Enrolled patients (n= 38) Randomized patients (n= 29) Treated patients (n= 5) Screening failures (n= 48; 26%) Waiting randomization (n= 9) Waiting initiation (n= 4) Completed (n= 20) Ongoing (n= 78) Withdrawn patients (n= 7; 4.8%) Adverse events (n= ) Consent withdrawn (n= ) Other (n=5) 0

11 Enrolled patients: Baseline demographics Total Enrolled (N=38) Age (yrs.) N Mean (SE) SD Median (min, max) (0.689) (53.0, 85.0) Age group (n, %) < >75 Missing 40 (29.0) 58 (42.0) 40 (29.0) Sex (n, %) Height (cm) Weight (cm) Male Female N Mean (SE) SD Median (min, max) N Mean (SE) SD Median (min, max) 68 (49.3) 70 (50.7) (0.823) (42.0, 82.9) (.090) (40.0, 7.)

12 Treatment feasibility Number of procedures performed at present: about 2,500 (approx.,875 real procedures) Number of procedures for the interim analysis:,367 procedures on 5 patients (approx.,025 real procedures) 652 Total Plasma Exchange procedures performed on 5 patients. 02 patients out of 5 (85%) underwent the 6 TPE procedures 75 Low Volume Plasma Exchange procedures performed on 96 patients. 20 patients underwent 2 LVPE procedures. 78 patients ongoing 2

13 Safety: The most frequent AEs SOC Number of AEs during the plasmapheresis periods n (%) Number of patients with AEs n (%) Number of AEs occurred n (%) Nervous system disorders Dizziness Presyncope Syncope 62 (4.54) 5 (.0) 3 (0.95) 2 (0.88) 43 (37.4) 3 (.3) 2 (0.4) 0 (8.7) 68 (3.) 6 (3.) 5 (2.9) 2 (2.3) General disorders and administration site conditions Catheter site related Infusion site related Thrombosis in device 76 (5.56) 22 (.6) 24 (.76) 42 (36.5) 24 (20.9) 5 (4.3) 83 (6.0) 28 (5.4) 0 (.9) (0.2) Blood and lymphatic system disorders Anaemia Iron deficiency anaemia 4 (3.00) 32 (2.34) 5 (0.37) 33 (28.7) 26 (22.6) 5 (4.3) 42 (8.) 32 (6.2) 5 (.0) Infections and infestations Catheter related 38 (2.78) 7 (0.5) 32 (27.8) 7 (6.) 39 (7.5) 7 (.3) Vascular disorders Hypotension 47 (3.44) 34 (2.49) 32 (27.8) 7 (4.8) 58 (.2) 34 (6.5) Musculoskeletal and connective tissue disorders Muscle spasms 36 (2.63) 26 (.90) 25 (2.7) 4 (2.2) 43 (8.3) 28 (5.4) Metabolism and nutrition disorders Hypocalcaemia Hypovolaemia 8 (.32) 4 (0.29) 4 (0.29) 4 (2.2) 4 (3.5) 4 (3.5) 8 (3.5) 4 (0.8) 4 (0.8) Cardiac disorders Bradycardia 7 (0.5) 6 (0.44) (9.6) 5 (4.3) 3 (2.5) 7 (.3) 3 Total of procedures:,367 Total of patients: 5 Total of AEs: 520

14 Safety: SAEs SOC Number of SAEs during the plasmapheresis periods n (%) Number of patients with SAEs n (%) Number of SAEs occurred n (%) Infections and infestations Device related infection Device related sepsis Endocarditis staphylococcal Lobar pneumonia Sepsis 5 (0.37) 5 (4.3) 5 (29.4) General disorders and administration site conditions Intentional medical device removal by patient Non-cardiac chest pain Pyrexia Thrombosis in device 3 (0.22) 0 (0.00) 4 (3.5) 4 (23.5) Nervous system disorders Lacunar infarction Metabolic encephalopathy Syncope 3 (0.22) 3 (2.6) 3 (7.6) Gastrointestinal disorders Large intestinal perforation Pancreatitis acute 2 (0.5) 2 (.7) 2 (.8) Eye disorders Retinal detachment Injury, poisoning and procedural complications Hip fracture Metabolism and nutrition disorders Hypovolaemia 4 Total of procedures:,367 Percentage of SAEs:.2% Total of patients: 5 Total of SAEs: 7

15 Outcome measure: MMSE, change from baseline Percentage of patients that improve/worsen (all patients, randomization code not broken) TPE LVPE 45.2% 33.3% 27.3% 30.3% 25.8% Cut-off: 0 points 54.8% 66.7% 72.7% 69.7% 74.2% Month 2 (N=04) Month 6 (N=70) Month 9 (N=44) Month 2 (N=35) Month 4 (N=3) Visits Improvement Worsening 5

16 Outcome measure: MMSE, change from baseline Percentage of patients that improve/worsen (-2 points) TPE LVPE 7.2% 52.2% 45.5% 5.5% 38.7% Cut-off: 2 points 28.8% 47.8% 54.5% 48.5% 6.3% Month 2 (N=04) Month 6 (N=70) Month 9 (N=44) Visit Month 2 (N=35) Improvement Month 4 (N=3) Worsening 6

17 Outcome measure: ADAS-Cog, changes from baseline Percentage of patients that improve/worsen (all patients, randomization code not broken) TPE LVPE 33.7% 45.7% 38.6% 29.4% 26.7% Cut-off: 0 points 66.3% 54.3% 6.4% 70.6% 73.3% Month 2 (N=04) Month 6 (N=70) Month 9 (N=44) Visits Month 2 (N=35) Improvement Month 4 (N=3) Worsening 7

18 Outcome measures: ADAS-Cog, changes from baseline Percentage of patients that improve/worsen (3 points) TPE 63.5% 64.3% LVPE 47.7% 50.0% 46.7% Cut-off: 3 points 36.5% 35.7% 52.3% 50.0% 53.3% Month 2 (N=04) Month 6 (N=70) Month 9 (N=44) Visits Month 2 (N=35) Improvement Month 4 (N=3) Worsening 8

19 Outcome measure: ADCS-ADL, changes from baseline Percentage of patients that improve/worsen (all patients, randomization code not broken) TPE LVPE Cut-off: 0 points 50.9% 40.0% 3.8% 36.4% 4.4% 49.% 60.0% 68.2% 63.6% 58.6% Month 2 (N=04) Month 6 (N=70) Month 9 (N=44) Month 2 (N=35) Month 4 (N=3) Visits Improvement Worsening 9

20 Summary The AMBAR trial has recruited 345 out of 364 patients (94%) in 39 sites (Spain and US) as of April 206. About 2,500 apheresis procedures (approx.,875 real) Interim data presented of the86 patients recruited as of June 205 (/2 sz) Close to,400 apheresis procedures performed (approx.,025 real) Randomization code not broken. Treatment is feasible with an acceptable adverse event profile. Main outcome measures show promising improvement/worsening rates (global). 20 2

21 Thank you! 2