Efficacy and Safety of Plasma Exchange With Albutein® 5% in Participants With Amyotrophic Lateral Sclerosis

This is a phase 2, prospective, open-label, single-arm pilot study to evaluate the efficacy and safety of PE with Albutein® 5% in participants with ALS. The planned enrollment is 10 participants who have a definite, possible, or probable diagnosis of ALS, according to the revised El Escorial criteria. Enrolled participants will be treated with PE using Albutein 5% as a replacement solution during an Intensive Treatment Phase (2 PEs per week over 3 weeks) followed by a Maintenance Treatment Phase (weekly PE for 21 weeks) for a total treatment duration of 6 months. A 6-month follow up will begin after the last PE.

• Albutein 5% (Biological), also known as Albutein 5% solution for perfusion: Albutein is manufactured from human plasma. The dose of Albutein 5% for replacement following plasma removal will be calculated based on gender, weight, and the hematocrit of the participant.
• Plasma Exchange (Procedure): Plasma Exchange will be performed using albutein 5% as the replacement solution.

Primary outcomes

• Change From Baseline in the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) Score [Baseline (Week 0), Weeks 4, 12, 25, 36, and 48]: The ALSFRS-R includes 12 questions to assess the self-sufficiency of participants in 3 sub-domains: bulbar function (questions 1-3), fine and gross motor function (questions 4-9), and respiratory function (question 10-12). Aspects of nourishment, personal care, personal autonomy, and communication were also evaluated. Each task was graded on a five-point scale from 0 (incapable) to 4 (normal ability), with total score range from 0 (worst) to 48 (best). A positive change from Baseline indicates improvement.
• Change From Baseline in Percent Predicted Forced Vital Capacity (FVC) [Baseline (Week 0), Weeks 4, 12, 25, 36, and 48]: The FVC measured the volume of air that can forcibly be exhaled through a spirometer after a full inspiration. It was expressed in a percentage of actual FVC over the expected FVC result in the general population, calculated as: Percent predicted FVC (in %) = \[(observed FVC in liters)/(predicted FVC in liters)\]*100.

Secondary outcomes

• Change From Baseline in Cognitive Function as Assessed by Behaviour Status Sub-scale Score of the Amyotrophic Lateral Sclerosis - Cognitive Behavioural Screen (ALS-CBS) Test [Baseline (Week 0), Weeks 25, and 48]: ALS-CBS test is composed of two sections: the cognitive screening section and behavioural changes section. The section of behavioural changes consists of behaviour status and symptom status sub-scales. Behaviour status sub-scale consists of a questionnaire with 15 items assessed by the caretaker. Each item was scored on a scale ranging from 0 (worst) to 3 (best) yielding a total 0= large changes to 45= no changes. A positive change from Baseline indicates improvement.
• Change From Baseline in Cognitive Function as Assessed by Symptom Status Sub-scale Score of the Amyotrophic Lateral Sclerosis - Cognitive Behavioral Screen (ALS-CBS) Test [Baseline (Week 0), Weeks 25, and 48]: ALS-CBS test is composed of two sections: cognitive screening section and behavioural changes section. The section of behavioural changes consists of behaviour status and symptom status sub-scales. Cognitive function assessed by symptom status sub-scale is reported, which consists of 4 additional questions related to current behavioural symptoms (depression, anxiety, fatigue, and emotional liability). Each question was scored as 0= the presence of symptoms and 1= no current symptoms, giving a total subscale score between 0 and 4. A positive change from Baseline indicates improvement.
• Change From Baseline in Cognitive Function as Assessed by Cognitive Screening Section Score of the Amyotrophic Lateral Sclerosis - Cognitive Behavioral Screen (ALS-CBS) Test [Baseline (Week 0), Weeks 25, and 48]: ALS-CBS test is composed of two sections: cognitive screening section and behavioural changes section. Cognitive function is evaluated using cognitive screening section which consists of: attention (complex orders, mental sums, language, and eye movement); concentration (inversion of numeric series); follow-up and monitoring (reverse sequences, alphabet, number and letter sequencing); and initiation and recovery (nomination). The individual items were scored from 0-5, and the total score ranges from 0-20, where 0= cognitive impairment, 20= no apparent cognitive impairment. A positive change from baseline indicates improvement.
• Change From Baseline in the Motor Evoked Potential in Thenar and Hypothenar Eminence and Anterior Tibialis Muscle Determined by Electromyography (EMG) [Baseline (Week 0), Weeks 4, 12, 25, 36, and 48]: Surface EMG was performed to record motor evoked potential in the distal muscles of the upper limbs (thenar and hypothenar eminence) and dorsiflexor muscles of the lower limbs (anterior tibialis) after electrical stimulation on the median, ulnar, and external popliteal sciatic nerve. The data for motor evoked potential (in millivolt \[mv\]) is reported for thenar muscles of both upper limbs and hypothenar muscle of the upper right limb and anterior tibialis of the both lower limbs.
• Evaluation of Quality of Life Using the Amyotrophic Lateral Sclerosis Assessment Questionnaire 40 (ALSA-Q40) Test Dimension Score [Weeks 25 and 48]: The ALS questionnaire consists of 40 items grouped into 5 representative dimensions associated with quality of life. The first four dimensions were: physical mobility (questions 1-10), activities of daily living (questions 11- 20), food and drink (questions 21-23), communication (questions 24-30) and emotional function (questions 31-40), refer to deficits and subsequent disabilities as a result of the disease. The fifth scale (emotional functioning) reflects how the participant is facing his/her physical deterioration emotionally. Each item is scored from 0 to 4 according to a gradation of symptom onset frequency (never, rarely, sometimes, often, always). From raw scores, an index from 0 to 100 is obtained for each dimension, which make comparisons with the other dimensions possible as well as a straightforward interpretation of the results (0 = better state of health as measured by the questionnaire;100 = poorer state of health). A negative change from Baseline indicates improvement.
• Change From Baseline in Plasma Human Apolipoprotein Levels [Baseline (Week 0), before and after PE procedure at Weeks 4, 12, 24, and before PE for Weeks 36 and 48]: The levels of human Apolipoprotein (ApoE) in plasma were measured by enzyme-linked immunosorbent assay (ELISA).
• Change From Baseline in Plasma Cytokine Panel Levels [Baseline (Week 0), before and after PE procedure at Weeks 4, 12, 24, and before PE for Weeks 36 and 48]: The plasma cytokine panel includes: transforming growth factor (TGF) beta1, TGF beta2, TGF beta3, interferon (IFN) gamma, interleukins (IL)-1beta, IL-1Ra, IL-6, IL-8, IL-10, IL-12 p70, IL-17A, IFN-γ-inducible protein (IP)-10, human monocyte chemoattractant protein (MCP)-1, macrophage-derived chemokine (MDC), macrophage inflammatory protein (MIP)-1-alpha, MIP-1-beta, tumor necrosis factor (TNF)-alpha, soluble cluster of differentiation (CD) 40 ligand (sCD40L), fractalkine. The level of each of these cytokines are reported as categories. Only categories with values above the level of detection are reported.
• Change From Baseline in Cerebrospinal Fluid (CSF) Human Apolipoprotein Levels [Baseline (Week 0), Weeks 12, and 25]: The levels of human Apolipoprotein (ApoE) in CSF were measured by enzyme-linked immunosorbent assay (ELISA).
• Change From Baseline in CSF Cytokine Panel Levels [Baseline (Week 0), Weeks 12, and 25]: The CSF cytokine panel includes: TGF beta1, TGF beta2, TGF beta3, IFN gamma, IL-1beta, IL-1Ra, IL-6, IL-8, IL-10, IL-12 p70, IL-17A, IP-10, MCP-1, MDC, MIP-1 alpha, MIP-1 beta, TNF alpha, sCD40L, fractalkine. The level of each of these cytokines are reported as categories. Only categories with values above the level of detection are reported.
• Change From Baseline in Plasma Beta-methylamino-L-alanine (BMAA) Levels [Baseline (Week 0), before and after PE procedure at Weeks 4, 12, 24, and before PE for Weeks 36 and 48]: Plasma BMAA levels at baseline and over the course of treatment at each evaluation visit were measured to identify reductions in BMAA levels, which could potentially be correlated with disease progression or a halt in disease progression. Analysis was performed using a Thermo TSQ Quantiva triple-stage quadrupole mass spectrometer.
• Change From Cerebrospinal Fluid (CSF) Beta-methylamino-L-alanine (BMAA) Levels [Baseline (Week 0), Weeks 12, and 25]: CSF BMAA levels at baseline and over the course of treatment at each evaluation visit were measured to identify reductions in BMAA levels, which could potentially be correlated with disease progression or a halt in disease progression. Analysis was performed using a Thermo TSQ Quantiva triple quadrupole mass spectrometer.
• Change From Baseline in Absolute Leukocyte Count [Baseline, Weeks 4, 12, and 48]: The immune population profile in ALS participants was assessed by flow cytometry following whole blood staining by Western Blot (WB) for the absolute leukocyte count. Absolute leukocyte count (10\^3 cells/microliter) was analyzed for neutrophils, lymphocytes, CD14+ monocytes, CD3+CD4+ T cells, CD3+CD8+ T cells, CD19+ B cells and CD56+ natural killer (NK) cells.
• Change From Baseline in Immune Population Profile [Baseline, Weeks 4, 12, and 48]: The immune population profile includes: Leukocyte panel (neutrophils, lymphocytes, CD14+ monos, CD3+CD4+ T cells, CD3+CD8+ T cells, CD19+ B cells, CD56+ NK cells). Regulatory T cells (Treg panel) (CD4+FoxP3+CD127low/, CD4+FoxP3+CD127low/-CD39+, CD4+FoxP3+CD127low/-CD45RA, CD4+FoxP3+CD127low/-CD152+), Myeloid-Derived Suppressor Cells (MDSC) (panel: CD14+CD15- monocytic MDSCs, CD14+CD15- monocytic MDSCs, CD124+ monocytic MDSCs, CD14-CD15+ granulocytic MDSCs, CD124+ granulocytic MDSCs, CD14-CD15- immature MDSCs, CD124+ immature MDSCs), Monocyte panel (CD14+CD16+, CD14+human leukocyte antigen-D related (HLA-DR)+ CD11b, CD14+HLA-DR+ CD163+, CD14+HLA-DR+ CX3CR1+). Data for each of these were reported as categories. Only categories with values above the level of detection are reported.
• Change From Baseline in Plasma Neurofilament Levels [Baseline (Week 0), before and after PE procedure at Weeks 4, 12, 24, and before PE for Weeks 36 and 48]: Levels of neurofilaments: Phosphorylated Neurofilament heavy chain (pNF-H) and Neurofilament light chain (NF-L) were measured by Enzyme-Linked Immunosorbent Assay (ELISA).
• Change From Baseline in Cerebrospinal Fluid (CSF) Neurofilament Levels [Baseline (Week 0), Weeks 12, and 25]: Levels of neurofilaments: Phosphorylated Neurofilament heavy chain (pNF-H) and Neurofilament light chain (NF-L) were measured by Enzyme-Linked Immunosorbent Assay (ELISA).

Other outcomes

• Percentage of PE Sessions Associated With at Least One Adverse Reaction (AR) [During or within 72 hours after the completion of the product infusion]
• Percentage of PE Sessions Associated With at Least One Adverse Event (AE), Irrespective of Causality [During or within 72 hours after the completion of the product infusion]
• Incidence of All AEs [Weeks -2 to 48]

Sex: All, ages: 19 Years to 69 Years

Inclusion Criteria:

* Signed informed consent
* Subjects over 18 years of age and less than 70 years old
* Subjects with a possible, probable-lab supported, probable, or definite diagnosis of Amyotrophic Lateral Sclerosis (ALS), according to the revised El Escorial criteria
* Subjects having experienced their first ALS symptoms within 18 months prior to recruitment/consent
* Forced Vital Capacity > 70%
* Subjects must be medically suitable for study participation and willing to comply with all planned aspects of the protocol, including blood sampling, at the time of inclusion in the study.

Exclusion Criteria:

* Subjects with pre-existing clinically significant lung disease not attributable to ALS
* Subjects diagnosed with other neurodegenerative diseases or diseases associated with other motor neuron dysfunction
* Participation in another investigational product study within one month prior to screening
* Females who are pregnant, breastfeeding, or, if of child-bearing potential, unwilling to practice a highly effective method of contraception (oral, injectable or implanted hormonal methods of contraception, placement of an intrauterine device or intrauterine system, condom or occlusive cap with spermicidal foam/ gel/ film/ cream/ suppository, male sterilization, or true abstinence) throughout the study
* Difficult or problematic peripheral vein access and inability to implant a central catheter which would make continuous Plasma exchange (PE) not feasible as per the visit protocol
* Contraindication to undergo PE or subject has abnormal coagulation parameters at the discretion of the Outpatient Apheresis Unit team, including but not limited to:

  1. Thrombocytopenia (platelets <100,000/ microliter \[μL\])
  2. Fibrinogen <1.5 gram per liter (g/L)
  3. International Normalized Ratio >1.5
  4. Beta-blocker treatment and bradycardia <50 beats/min
  5. Treatment with angiotensin-converting enzyme inhibitors which may increase the risk of allergic reactions, unless a preventive change in hypotensive treatment occurs prior to enrollment
* History of anaphylaxis or severe systemic response to any plasma-derived albumin preparation, component of Albutein® 5%, or other blood product(s)
* Subjects unable to interrupt treatment with acetylsalicylic acid, other oral antiplatelet, or anticoagulant
* Renal dysfunction by elevated creatinine concentration >2 milligram per deciliter (mg/dL)
* Presence of heart disease that contraindicates PE treatment, including ischemic cardiopathy and congestive heart failure
* Presence of prior behavioural disorders requiring pharmacological intervention with less than 3 months of stable treatment
* Mentally challenged subject who cannot give independent informed consent
* Any condition that would complicate compliance with the study protocol (i.e., illness with the expectation of less than one year survival, abuse of drugs or alcohol, etc.)

Participant flow

Outcome results

• Change From Baseline in the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) Score (Primary), Mean, units on scale: Albutein 5% 39.8 +/- 5.88
• Change From Baseline in Percent Predicted Forced Vital Capacity (FVC) (Primary), Mean, percentage of predicted FVC: Albutein 5% 89.7 +/- 16.26
• Change From Baseline in Cognitive Function as Assessed by Behaviour Status Sub-scale Score of the Amyotrophic Lateral Sclerosis - Cognitive Behavioural Screen (ALS-CBS) Test (Secondary), Mean, units on a scale: Albutein 5% 41.7 +/- 3.44
• Change From Baseline in Cognitive Function as Assessed by Symptom Status Sub-scale Score of the Amyotrophic Lateral Sclerosis - Cognitive Behavioral Screen (ALS-CBS) Test (Secondary), Mean, units on scale: Albutein 5% 3.5 +/- 0.69
• Change From Baseline in Cognitive Function as Assessed by Cognitive Screening Section Score of the Amyotrophic Lateral Sclerosis - Cognitive Behavioral Screen (ALS-CBS) Test (Secondary), Mean, units on scale: Albutein 5% 16.4 +/- 5.12
• Change From Baseline in the Motor Evoked Potential in Thenar and Hypothenar Eminence and Anterior Tibialis Muscle Determined by Electromyography (EMG) (Secondary), Mean, millivolt (mV): Albutein 5% 4.1 +/- 2.36
• Evaluation of Quality of Life Using the Amyotrophic Lateral Sclerosis Assessment Questionnaire 40 (ALSA-Q40) Test Dimension Score (Secondary), Mean, units on a scale: Albutein 5% 23.6 +/- 17.61
• Change From Baseline in Plasma Human Apolipoprotein Levels (Secondary), Mean, nanogram per milliliter (ng/mL): Albutein 5% 6753.8 +/- 3549.07
• Change From Baseline in Plasma Cytokine Panel Levels (Secondary), Mean, picogram per milliliter (pg/mL): Albutein 5% 9998.9 +/- 5811.61
• Change From Baseline in Cerebrospinal Fluid (CSF) Human Apolipoprotein Levels (Secondary), Mean, ng/mL: Albutein 5% 3877.7 +/- 1479.73
• Change From Baseline in CSF Cytokine Panel Levels (Secondary), Mean, pg/mL: Albutein 5% 224.73 +/- 36.830
• Change From Baseline in Plasma Beta-methylamino-L-alanine (BMAA) Levels (Secondary), Mean, ng/mL: Albutein 5% NA +/- NA
• Change From Cerebrospinal Fluid (CSF) Beta-methylamino-L-alanine (BMAA) Levels (Secondary), Mean, ng/mL: Albutein 5% NA +/- NA
• Change From Baseline in Absolute Leukocyte Count (Secondary), Mean, 10^3 cells/microliter: Albutein 5% 4.18 +/- 1.359
• Change From Baseline in Immune Population Profile (Secondary), Mean, percentage of CD45+ cells: Albutein 5% 68.13 +/- 11.672
• Change From Baseline in Plasma Neurofilament Levels (Secondary), Mean, ng/mL: Albutein 5% 7.26 +/- 5.811
• Change From Baseline in Cerebrospinal Fluid (CSF) Neurofilament Levels (Secondary), Mean, ng/mL: Albutein 5% 0.68 +/- 0.147
• Percentage of PE Sessions Associated With at Least One Adverse Reaction (AR) (Other pre specified)
• Percentage of PE Sessions Associated With at Least One Adverse Event (AE), Irrespective of Causality (Other pre specified)
• Incidence of All AEs (Other pre specified)

Adverse events

Time frame: From the start of study treatment until end of study (Up to Week 48)

Serious adverse events by term

Other adverse events by term

12 more terms not shown.

• Study Protocol (PDF, 2016-05-05)
• Statistical Analysis Plan (PDF, 2019-04-29)