A Double-blind, Placebo-controlled, Exploratory Randomised Clinical Trial to Assess the Safety and Efficacy of IFB-088 Plus Riluzole 100 mg vs Placebo Plus Riluzole 100 mg in Patients With Bulbar-onset Amyotrophic Lateral Sclerosis.
Phase: PHASE2
Conditions: Amyotrophic Lateral Sclerosis, ALS
Sponsor: InFlectis BioScience

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Study Protocol
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CONFIDENTIAL                                               TRIALS study
InFlectis BioScience
STUDY PROTOCOL
A double-blind, placebo-controlled, exploratory randomised clinical
trial to assess the safety and efficacy of IFB-088 plus riluzole 100 mg
vs placebo plus riluzole 100 mg in patients with bulbar-onset
amyotrophic lateral sclerosis
Treatment combining Riluzole and IFB-088 in bulbar Amyotrophic
Lateral Sclerosis: the TRIALS study
Protocol number
EUDRACT number
Protocol date
Protocol version
Investigational product
name
Indication
Sponsor
P288ALS
2021-003875-32
08 April 2024
Version 4.0 (Final)
IFB-088
Bulbar-onset amyotrophic lateral sclerosis
InFlectis BioScience
21 Rue La Noue Bras de Fer, 44200 Nantes, France
Sponsor signatory: Anne Visbecq, MD, Chief Medical
Officer. Tel: +33 6 30 63 20 20
Sponsor medical expert: Anne Visbecq, MD, Chief
Medical Officer. Tel: +33 6 30 63 20 20
Coordinating / Principal
investigator(s)
Principal investigator: Pr Shahram Attarian, head of
Department of neurology and neuromuscular disorders,
Assistance Publique Hôpitaux de Marseille, Marseille,
France. Shahram.ATTARIAN@ap-hm.fr.
Tel: +33 4 91 38 65 79
Co-principal investigator for Italy: Pr Giuseppe Lauria,
Department of clinical neurosciences, IRCCS Carlo
Besta
Institute
of
Milan,
Milan,
Italy.
Giuseppe.LauriaPinter@istituto-besta.it.
Tel: (+39) 02.2394.4018
Contract Research
Organisation (CRO)
(Monitor)
Keyrus Life Science (KLS), 155 rue Anatole France,
92300 Levallois Perret, France. Tel: +33 1 41 34 10 00
CONFIDENTIAL: This document is property of InFlectis BioScience and contains
confidential information. It may not be forwarded to third parties without explicit written
prior consent from InFlectis BioScience. Reproductions, either in part or in whole, may not
be published or copied in any manner, without the explicit written consent of InFlectis
BioScience.
08-Apr-2024
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STUDY ADMINISTRATIVE STRUCTURE
Sponsor
Coordinating / Principal investigator(s)
InFlectis BioScience
21 Rue La Noue Bras de Fer, 44200
Nantes, France
Sponsor signatory: Anne Visbecq, MD,
Chief Medical Officer.
Tel: +33 6 30 63 20 20
Principal
investigator:
Pr
Shahram
Attarian,      head
of      Department
of
neuromuscular      disorders      and      ALS,
Assistance       Publique       Hôpitaux       de
Marseille,             Marseille,             France.
Shahram.ATTARIAN@ap-hm.fr
Tel: +33 4 91 38 65 79
Co-Principal investigator for Italy: Pr
Giuseppe Lauria, Department of clinical
neurosciences,
IRCCS
Carlo
Besta
Institute
of      Milan,      Milan,      Italy.
Giuseppe.LauriaPinter@istituto-besta.it
Tel: (+39) 02.2394.4018
Sponsor medical expert
Project manager
Anne
Visbecq,
MD,
Chief
Medical
Officer. Tel: +33 6 30 63 20 20
KLS project manager
155 rue Anatole France, 92300 Levallois
Perret, France
Clinical research associate (CRA)
Medical writer
Pharmacovigilance
08-Apr-2024
Phone: +33 1 41 34 10 00
KLS CRA
KLS medical writer
Drève Richelle 161, Bât L, 1410,
Waterloo, Belgium
Phone: +32 2 627 51 30
STRAGEN Services SAS
19 rue Jacqueline Auriol, 69008 Lyon,
France
Phone : +33 4 78 42 95 26
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Study Protocol
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InFlectis BioScience
PROTOCOL SPONSOR SIGNATURE PAGE
A double-blind, placebo-controlled, exploratory randomised clinical
trial to assess the safety and efficacy of IFB-088 plus riluzole 100 mg
vs placebo plus riluzole 100 mg in patients with bulbar-onset
Amyotrophic Lateral Sclerosis
Treatment combining Riluzole and IFB-088 in bulbar Amyotrophic
Lateral Sclerosis: the TRIALS study
Protocol number
EUDRACT number
Protocol date
Sponsor
P288ALS
2021-003875-32
08 April 2024
Anne Visbecq, MD
Chief Medical Officer
Tel: +33 6 30 63 20 20
InFlectis BioScience
21 Rue La Noue Bras de Fer, 44200 Nantes,
France
Date
12/4/2024
Signature
08-Apr-2024
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Study Protocol
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PROTOCOL INVESTIGATOR SIGNATURE PAGE
A double-blind, placebo-controlled, exploratory randomised clinical
trial to assess the safety and efficacy of IFB-088 plus riluzole 100 mg
vs placebo plus riluzole 100 mg in patients with bulbar-onset
Amyotrophic Lateral Sclerosis
Treatment combining Riluzole and IFB-088 in bulbar Amyotrophic
Lateral Sclerosis: the TRIALS study
Protocol number
EUDRACT number
Protocol date
P288ALS
2021-003875-32
08 April 2024
I certify that I will conduct the study in compliance with the protocol, any amendments,
GCP and all applicable regulatory requirements.
Investigator
Institution
Pr Shahram Attarian
Head of Department of neuromuscular disorders
and ALS.
Assistance Publique Hôpitaux de Marseille,
Marseille, France.
Date 
12/4/2024
Signature
08-Apr-2024
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Study Protocol
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CONFIDENTIAL                                               TRIALS study
InFlectis BioScience
PROTOCOL INVESTIGATOR SIGNATURE PAGE
A double-blind, placebo-controlled, exploratory randomised clinical
trial to assess the safety and efficacy of IFB-088 plus riluzole 100 mg
vs placebo plus riluzole 100 mg in patients with bulbar-onset of
Amyotrophic Lateral Sclerosis
Treatment combining Riluzole and IFB-088 in bulbar Amyotrophic
Lateral Sclerosis: the TRIALS study
Protocol number
EUDRACT number
Protocol date
P288ALS
2021-003875-32
08 April 2024
I certify that I will conduct the study in compliance with the protocol, any amendments,
GCP and all applicable regulatory requirements.
Investigator
Institution
Pr Giuseppe Lauria
Department of clinical neurosciences.
IRCCS Carlo Besta Institute of Milan, Milan,
Italy.
Date 
15/4/2024
Signature
08-Apr-2024
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SYNOPSIS
Protocol number: P288ALS
EUDRACT number: 2021-003875-32
Indication:
Amyotrophic
Lateral
Phase: Phase II
Sclerosis (ALS)
Investigational product: IFB-088,
Active ingredient: IFB-088
tablets
Protocol date: 08 April 2024
Sponsor: InFlectis BioScience
Study title:
Rationale for the
study:
A double-blind, placebo-controlled, exploratory randomised clinical trial to assess
the safety and efficacy of IFB-088 plus riluzole 100 mg vs placebo plus riluzole 100
mg in patients with bulbar-onset amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of
motor neurons in the brain and spinal cord, resulting in progressive paralysis, with
death typically occurring within 2 to 4 years of symptom onset. The prognosis has
not been very much improved by the only approved medication in Europe, riluzole.
ALS can be divided into 2 onsets, namely spinal and bulbar, the latter being
characterised by difficulties in swallowing, chewing and speaking, a more rapid
evolution and a poorer prognosis. It has been demonstrated that targeting the
unfolded protein response (UPR) pathway, in particular the phosphatase complex
protein
phosphatase
1
regulatory
subunit
15A/protein
phosphatase
1c
(PPP1R15A/PP1c) could be beneficial to ALS patients. IFB-088 is a
PPP1R15A/PP1c phosphatase complex inhibitor that has demonstrated activity in
the so far best studied animal model of ALS, i.e. transgenic rodents overexpressing
the gene encoding superoxide dismutase 1 (SOD-1). Similarly, another
PPP1R15A/PP1c phosphatase complex inhibitor, guanabenz, also demonstrated
benefits in ALS animal models. The 2 molecules have the same pharmacological
target but guanabenz also exhibits α2 adrenergic activity responsible for lowering
blood pressure (the drug has been commercialised as an anti-hypertensive drug in
several countries). IFB-088 has been shown to be devoid of this α2 adrenergic
activity and demonstrated a good safety profile in a phase I study in healthy
volunteers as no toxicity signal has been detected at any doses evaluated, including
single daily doses up to 60 mg and repeated daily doses up to 50 mg for 14 days.
Guanabenz has been investigated in an exploratory phase II study in ALS patients.
It showed encouraging results, especially in patients with bulbar-onset ALS. The
incidence of hypotension in this study discouraged further development in ALS.
Since a similar efficacy is expected for IFB-088 without hypotensive effects, an
exploratory study has been designed to assess the safety and the efficacy of IFB-088
in patients with bulbar-onset ALS.
Objectives
endpoints:
and
Primary objective
To assess the safety of IFB-088 50 mg/day in patients with bulbar-onset ALS.
Primary endpoints
Safety endpoints include:
·
Incidence, grade and relationship to IFB-088 for treatment emergent AEs,
SAEs, and AESIs,
·
AEs leading to dose interruption or premature discontinuation.
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InFlectis BioScience
Secondary objectives
·
To assess the efficacy of IFB-088 50 mg/day plus riluzole 100 mg/day
versus placebo plus riluzole 100 mg/day over a 6-month period in patients
with bulbar-onset ALS,
·
To determine pharmacokinetics (PK) parameters of IFB-088,
·
To investigate the effects of IFB-088 on ALS potential biomarkers,
·
To investigate quality of life (QoL).
Secondary and exploratory endpoints
Efficacy:
·
Change in Revised ALS functional rating scale (ALSFRS-R) score from
baseline to month 3 and to month 6,
·
Worsening according to ALS-Milano-Torino staging system (MITOS)
score, i.e. progression to a higher stage at 3 and at 6 months compared to
the baseline,
·
Change in King’s College score from baseline to month 3 and to month 6,
·
Assessment of respiratory function (slow vital capacity [SVC], sniff test
[optional], arterial blood gases [ABG]): exploratory endpoint.
·
Evaluation of nutritional status and body composition by bioelectrical
impedance: exploratory endpoint
PK parameters:
·
Plasma concentration of IFB-088 and IFB-139,
·
AUC of IFB-088 and IFB-139,
·
Maximum observed plasma concentration (Cmax), with associated Tmax,
·
Terminal or apparent terminal half-life (t1/2),
·
Apparent systemic clearance, apparent volume of distribution.
Biomarkers:
·
Change in TDP-43 plasmatic concentration from baseline to 6 months,
compared to placebo,
·
 Change in neurofilament (NfL) light chain and NfL heavy chain plasmatic
concentration from baseline to 6 months, compared to placebo,
·
Change in plasmatic (neuro)inflammatory biomarkers from baseline to 3
months, and from baseline to 6 months, compared to placebo,
·
Change in plasmatic oxidative stress biomarkers from baseline to 3 months
and from baseline to 6 months, compared to placebo.
QoL:
·
 Change in ALS assessment questionnaire (ALSAQ-40) from baseline to 6
months.
Study Population,
Countries and
sites:
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Adult patients with bulbar-onset ALS.
Patients will be recruited in France and in Italy.
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Study design:
 Prospective,
international,
randomised,
double-blind,
placebo
controlled,
multicentre, parallel group study.
Patients will be randomised in a 2:1 allocation ratio to receive either IFB-088 +
riluzole 100 mg or placebo + riluzole 100 mg.
Patients will be treated over a 6-month period. After a screening/consent visit,
patients will undergo clinic visits at randomisation (V0), at 2 weeks (V1), and at
months 1 (V2), 3 (V3), 4.5 (V3bis) and 6 (V4). In addition to these hospital visits,
patient will undergo urine analysis (dipstick) and blood sampling for measurement
of creatinine one week after V0, as well as blood sampling for measurement of
creatinine and calculation of eGFR at months 2, 4 and 5. At the V2 visit, in addition
to other assessments, patients will undergo blood sampling for PK measurements
and urine sampling for crystalluria examination. Laboratory parameters, as well as
physical examination and vital signs assessment to assess safety will be performed
at each visit for safety purpose and crystalluria examination will be repeated at the
follow-up visit, performed one month ± one week after V4, or in case of premature
discontinuation.
Safety will be monitored over the course of the study by a data and safety monitoring
board (DSMB).
If needed, compliance with coronavirus disease 2019 (COVID-19)-related rules will
be followed and adjustments might be necessary accordingly.
Unless they already obtained treatment research initiative to cure ALS (TRICALS)
certificates, study examiners will undergo online training to ensure uniformity of
study procedures across sites, and inter-rater variability will be documented. For
investigators who cannot undergo the TRICALS training, certification from the
Barrow Neurological Institute is acceptable.
Management of frail functions will be standardised as much as possible.
Planned
number
of patients:
The minimum required sample size for this study has been estimated at 42 evaluable
patients, 28 receiving IFB-088 and 14 receiving placebo. Assuming a 15% drop-out
rate, 50 patients will be randomised.
Investigational
products,
dose
and
mode      of
administration:
NAME
IFB-088
PLACEBO
PHARMACEUTICAL
FORM
Tablets
Tablets
UNIT DOSE
STRENGTH
25 mg
NA
MODE OF
ADMINISTRATION
Oral
Oral
IFB-088 and placebo will be provided as white, oblong, immediate release
tablets. IFB-088
and
placebo
tablets
contain
the
following
excipients:
microcrystalline cellulose, colloidal silica, crospovidone and magnesium stearate.
The drug product and placebo will be manufactured and formulated under current
good manufacturing practice (GMP) conditions. Tablets should be kept in the
containers provided to patients and stored at room temperature.
IFB-088 or placebo will be administered orally twice a day (morning and evening
uptakes), as an add-on therapy to riluzole 100 mg. Intervals for dosing should ideally
be about 12 hours (± one hour). Tablets will be swallowed with a glass of water 30
minutes before the meal, in fasting condition. For patients who have swallowing
difficulties, tablets will be administered in a spoon filled with jellified water to
prevent swallowing disorders.
Inclusion criteria:
Patients must satisfy all the following inclusion criteria:
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1.
Diagnosis of probable or definite ALS according to the revised El Escorial
criteria, with bulbar onset of disease, familial or sporadic form,
2.
Onset of symptoms ≤ 18 months prior to screening, as reported by the
patient,
3.
Adult males or females, aged at least 18 years old,
4.
SVC > 60% of predicted value for age and sex,
5.
ALSFRS-R score ≥ 36,
6.
Treatment with riluzole 100 mg/day, at stable dose since at least one month
and well tolerated,
7.
 Male or female patient of childbearing potential1 who agrees to use highly
effective
mechanical
contraception
methods
(sexual
abstinence,
intrauterine device, bilateral tubal occlusion, vasectomised partner)
throughout the study, and for 3 months after the end of the treatment,
8.
Patient who read, understood and signed the informed consent form (ICF),
9.
 Patient who is willing to adhere to the study visit schedule and is capable
to understand and comply with protocol requirements.
Exclusion
criteria:
A patient will not be eligible for inclusion in this study if at least one of the
following criteria applies:
1.
Known other significant neurological disease(s),
2.
Serious illness(es) or medical condition(s) (e.g. unstable cardiac disease,
cancer, hematologic disease, hepatitis or liver failure, renal failure) that is
not stabilised or that could require hospitalisation and may jeopardise the
participation in the study,
3.
Abnormal renal function at screening defined as estimated glomerular
filtration rate (eGFR) < 60 mL/min/1.73m2,
4.
Abnormal liver function at screening defined as total bilirubin levels >1.5
ULN, and/or AST and/or ALT >3 ULN,
5.
Neutropenia (ANC <1.5 x 109/L) at screening,
6.
Other causes of neuromuscular weakness,
7.
 Non progressive or very rapidly progressing ALS (ALSFRS-R decline
from disease onset to randomisation ≤ 0.1 / month or ≥ 1.2 / month)2,
8.
Non-invasive ventilation,
9.
Tracheotomy,
1 According to the CTFG guideline V2.1 September 2020, a woman is considered of childbearing potential (WOCBP),
i.e., fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation
methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined
as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the
postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or
hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is
insufficient. A man is considered fertile after puberty unless permanently sterile by bilateral orchidectomy.
2 Decline will be calculated as follows: 48 minus ALSFRS-R score at the time of inclusion divided by number
of months since occurrence of first symptoms of disease, as reported by the patient.
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10. Dementia or other severe active psychiatric illness, including suicidal
ideation assessed using the Columbia-Suicide Severity Rating Scale (C-
SSRS),
11. Patient with a significant pulmonary disorder not attributed to ALS or who
require treatments that might complicate the evaluation of the effect of ALS
on respiratory function,
12. Patient treated by edaravone for ALS,
13. Patient using unauthorised concomitant treatments, namely moderate or
strong inhibitors or inducers of cytochrome P450 family 1 subfamily A
member 2 (CYP1A2), strong inhibitors or inducers of CYP2D6 or 2C19
and strong inhibitors of OCT2. Combined oral contraceptives containing
ethinylestradiol are forbidden concomitant medications,
14. Smoker of > 10 cigarettes per day (e-cigarettes and nicotine patches are
permitted),
15. Known hypersensitivity to any of the ingredients or excipients of the
investigational medicinal products (IMPs),
16. Pregnant, lactating women,
17. Patient who participated in another trial of investigational drug(s) within
30 days prior to randomisation, or 5 half-lives of the previous
investigational product, whichever is longer,
18. Patient who has forfeited their freedom by administrative or legal award,
or who is under guardianship or under limited judicial protection.
Evaluation
criteria:
Safety Assessments
Safety assessments will include the surveillance and recording of adverse events
(AEs) including serious adverse events (SAEs), treatment emergent AEs (TEAEs),
AEs of special interest (AESIs). Identified AEs will be characterised in relation to
seriousness, incidence, severity, and relationship to the study product.
The percentage of patients requiring dosing interruption or definitive treatment
discontinuation due to toxicity will be recorded.
Safety evaluation will be performed at all visits.
Efficacy Assessments
Clinical scores: changes between baseline and 3 months, and between baseline and
6 months will be calculated for:
·
ALSFRS-R score,
·
ALS- ALS-MITOS score,
·
King’s College score,
·
Respiratory function (SVC, sniff test, ABG).
·
Bioelectrical Impedance Analysis
PK assessments
Blood samples will be collected at V2 (5 samples/patient: pre-IMP dose, and at one,
2, 4 and 6 hours post dose). After processing, plasma samples will be stored at -
80°C pending analyses within the same week. IFB-088 and its main metabolite IFB-
139 concentrations will be measured using a validated high-performance liquid
chromatography with tandem mass spectrometry (HPLC/MS-MS) method.
Biomarker assessments
Blood potential biomarkers (neurofilament [NfL] light chain, NfL heavy chain, and
TAR DNA-binding protein 43 [TDP-43]) will be measured at baseline and 6 months
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InFlectis BioScience
while biomarkers of neuro-inflammation and oxidative stress will be measured in
blood at baseline, 3 and 6 months.
Blood, cerebrospinal fluid (CSF)3 and urine will be stored frozen in a biobank for
further biomarker analyses4.
Statistical
methods:
Statistical Methods
Statistical methods will be further detailed in the statistical analysis plan (SAP).
General considerations:
Statistical analysis will be performed by the sponsor or under the supervision of the
sponsor. Complete details of the statistical analyses will be provided in the SAP,
which will be finalised prior to the locking and unblinding of the database.
In general, summary tabulations will be presented by treatment arm and will display
the number of observations, mean, standard deviation (SD), median, Q1, Q3
quartiles minimum, and maximum for continuous variables, and the number and
percent per category for categorical data.
Nominal alpha level of significance: as it is an exploratory study, statistical tests will
be performed at the alpha one-sided level of 0.10. 80% and 95% 2-sided confidence
intervals (CIs) will be provided.
No adjustment for multiplicity issues will be considered.
Missing data handling: as a general rule, missing data will not be replaced.
Sensitivity analyses based on multiple imputation will be proposed and further
detailed in the SAP.
Baseline characteristics description:
Baseline characteristics will be described by treatment arm according to general
considerations.
Analysis sets:
The following analysis sets will be considered. Additional details of analysis sets
of patients may be defined in the SAP.
·
Safety set (SS): randomised patients having received at least one dose of
the IMPs and analysed according to the treatment actually received.
Efficacy sets:
·
Randomized Set (RS): all patients “as randomised” (i.e. according to the
treatment group to which they were randomised, regardless of the
treatment actually taken),
·
Full analysis set (FAS): as randomized patients having received at least
one dose of the IMPs and having a non-missing baseline value,
·
Per protocol set (PPS): FAS patients fulfilling the following criteria.
Criteria definition will be further detailed during a blinded data review
meeting and specified in the SAP:
o Major inclusion/exclusion criteria satisfied,
o Absence of relevant protocol violations likely to affect treatment
efficacy,
3 In patients willing to undergo lumbar puncture.
4 Patients will be asked in the ICF if they want to consent to the storage of their biological samples in the
biobank.
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o Adequate study medication compliance, defined as intake of at
least 80% of the planned total dose.
Primary Outcome:
Usual descriptive statistics will be used and detailed in the SAP to analyse the safety
parameters.
Secondary Outcomes:
Efficacy:
Analyses will be further detailed in the SAP. The analysis of efficacy endpoints will
be primarily performed in the FAS. A secondary analysis will be proposed in the
PPS.
·
 Change in ALSFRS-R score from baseline to 6 months: the change from
baseline to 6 months will be analysed using a mixed model for repeated
measures (MMRM) assuming missing at random (MAR) and an
unstructured covariance matrix and including fixed factors for treatment,
visit (categorical variable), treatment-by-visit interaction, random patient
factor and baseline ALSFRS-R as a continuous covariate. The degrees of
freedom will be estimated using the Kenward-Roger’s approximation. Least
square means (LSMs) of change from baseline and LSM differences in
change from baseline between active doses and placebo will be presented
along with 80% and 95% CIs and the comparison p-value. A one-sided
nominal significance level of 0.10 will be used for treatment comparison.
Model assumptions will be checked (plot of studentized residuals vs
predicted values, etc.). If the model assumptions do not hold, a rank semi-
parametric analysis of covariance (ANCOVA) model (or a rank non-
parametric Quade’s ANCOVA model if the assumptions of this latter do
still not hold) will be proposed instead. As the MAR assumption is
untestable and may not hold for subjects withdrawing at their own will, a
sensitivity analysis will be based on a pattern mixture model that uses a
multiple imputation technique analysed with an ANCOVA with pre-
specified fixed factors and covariates. The imputation model will be further
clarified in the SAP. In addition, a sensitivity Bayesian analysis using the
historical placebo data from E. Dalla Bella’s ProMISe study will be also
performed and further detailed in the SAP. An intrapatient analysis of
ALSFRS-R changes will be performed.
·
Worsening, i.e. progression to a higher stage at 6 months compared to the
baseline stage defined by ALS-MITOS score: the proportion of progressors
will be compared between both treatment groups. The difference in
binomial proportions will be estimated along with an exact 95% CI. A
sensitivity Bayesian analysis using the historical placebo data from Dalla
Bella’s et al. ProMISe study of 2021 will be also performed and further
detailed in the SAP. Progressors will also be analysed in a logistic
regression model adjusting for treatment, randomisation stage and
additional relevant covariates (specified in the SAP). The treatment effect
will be estimated in terms of an odds ratio associated with the 95% CI and
p-value and also in terms of a difference in progression rates with its 95%
CI using the method proposed by Ge and al. in 2011.
·
 Change in King’s College score: the endpoint will be analysed with an
approach similar to the analysis of ALS-MITOS score.
Analyses of the changes in efficacy endpoints from baseline to month 3 (as
inferential analysis) and from month 3 to month 6 (as descriptive analysis) will be
also proposed and further detailed in the SAP.
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·      Respiratory function: changes from baseline to 3 months and from baseline
to 6 months will be analysed. Further details will be provided in the SAP.
·
Bioelectrical impedance analysis: changes from baseline to 3 months and
from baseline to 6 months will be analysed for selected variables. Further
details will be provided in the SAP.
PK:
Individual plasma concentrations of IFB-088 and IFB-139 (i.e. IFB-088 metabolite)
with corresponding nominal sampling times, will be tabulated for each subject and
scheduled sampling time, together with descriptive statistics. Mean plasma IFB-088
concentrations profiles by cohort will be presented over time graphically, using
blood sampling time (x axis) and concentrations (y axis) on both linear and semi-
log scales. Derived and observed PK parameters will be evaluated by
noncompartmental analysis.
Plasma concentrations of IFB-088 will also be analysed using a population PK
modelling approach to develop a population PK model in patients with ALS.
PK and pharmacodynamic (PD) data will be listed and presented in graphical and/or
tabular form as appropriate to the data, and will be summarized descriptively. A
PK/PD model could be developed according to the available data.
Biomarkers:
Details of analysis will be provided in the SAP. Changes in plasma concentration
of TDP-43, NfL heavy chain and NfL light chain will be measured from baseline to
6 months.
Changes in plasma concentration of inflammatory and oxidative stress biomarkers
will be measured from baseline to 3 months, and from baseline to 6 months. All
changes will be compared between both arms.
Correlation of biomarkers with clinical endpoints will be assessed.
QoL:
Change in ALS-AQ40 QoL scores from baseline will be assessed at 6 months and
compared between both arms.
Sample size determination: The minimum required sample size for this study has
been estimated at 42 evaluable patients. Since it is an exploratory safety study, it has
not been based on a formal sample size calculation. However, with regard to the
primary safety endpoint, it is worth noting that 28 patients enrolled in the IFB-088
arm will be sufficient to observe at least one SAE which incidence is greater than or
equal to 5% (10% resp.) with a probability of at least 76.2% (94.8% respectively).
In addition, 42 patients are also considered sufficient to observe some numerical
efficacy signal on some key parameters. Assuming a 15% drop-out rate, 50 patients
will be randomised.
Study timelines:
08-Apr-2024
First patient in: first quarter 2022
Last patient out: third quarter 2024
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TABLE OF CONTENTS
STUDY ADMINISTRATIVE STRUCTURE .................................................................................. 2
PROTOCOL SPONSOR SIGNATURE PAGE ............................................................................... 3
PROTOCOL INVESTIGATOR SIGNATURE PAGE.................................................................... 4
PROTOCOL INVESTIGATOR SIGNATURE PAGE.................................................................... 5
SYNOPSIS....................................................................................................................................... 6
TABLE OF CONTENTS ............................................................................................................... 14
LIST OF TABLES......................................................................................................................... 17
LIST OF FIGURES ....................................................................................................................... 17
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS.................................................... 18
1.
1.1
1.1.1
1.1.2
1.2
1.3
2.
3.
3.1
3.2
3.3
3.4
3.5
3.6
3.7
3.8
3.9
3.9.1
4.
4.1
4.1.1
4.1.2
4.1.3
4.1.4
4.1.5
4.1.6
4.1.7
4.1.8
4.1.9
4.2
4.2.1
08-Apr-2024
INTRODUCTION.......................................................................................................... 23
BACKGROUND ..........................................................................................................................23
Amyotrophic lateral sclerosis..............................................................................................23
IFB-088...............................................................................................................................24
Preclinical studies ...................................................................................................................... 25
Clinical studies........................................................................................................................... 27
RATIONALE FOR THE STUDY .....................................................................................................27
BENEFIT-RISK ASSESSMENT......................................................................................................28
STUDY OBJECTIVES AND ENDPOINTS................................................................... 30
STUDY DESIGN............................................................................................................ 31
STUDY DESIGN OVERVIEW........................................................................................................31
RATIONALE FOR THE STUDY DESIGN.........................................................................................33
DOSE JUSTIFICATION ................................................................................................................33
STUDY DURATION.....................................................................................................................34
STUDY COMPLETION AND FOLLOW-UP......................................................................................35
PREMATURE TERMINATION OF THE STUDY................................................................................35
SCHEDULE OF ACTIVITIES .........................................................................................................35
IDENTIFICATION OF PATIENTS...................................................................................................38
RANDOMISATION AND BLINDING..............................................................................................38
Unblinding process .............................................................................................................38
Unblinding for emergency ......................................................................................................... 38
Unblinding for DSMB................................................................................................................ 39
Unblinding at the end of trial ..................................................................................................... 39
Unblinding by the pharmacovigilance and safety institution ..................................................... 39
STUDY VISITS AND PROCEDURES/ASSESSMENTS............................................... 39
STUDY VISITS............................................................................................................................39
Screening visit.....................................................................................................................39
Baseline – V0 visit..............................................................................................................41
V1 visit................................................................................................................................43
V2 visit................................................................................................................................43
V3 visit................................................................................................................................44
V3bis visit...........................................................................................................................45
V4 visit................................................................................................................................45
FU visit – V-FU ..................................................................................................................46
Premature discontinuation visit...........................................................................................47
SPECIFIC ASSESSMENTS ............................................................................................................48
Measurements of the primary variable................................................................................48
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4.2.2
5.
5.1
5.2
5.3
6.
6.1
6.1.1
6.1.2
6.1.3
6.1.4
6.2
6.3
6.4
7.
7.1
7.2
7.3
7.4
7.5
7.6
7.7
7.8
7.9
7.10
7.11
8.
8.1
8.1.1
8.1.2
8.1.3
8.1.4
8.1.5
9.
08-Apr-2024
Safety assessment....................................................................................................................... 48
Physical examination ................................................................................................................. 48
Neuropsychological assessment................................................................................................. 48
C-SSRS evaluation..................................................................................................................... 48
Vital signs .................................................................................................................................. 48
Electrocardiogram...................................................................................................................... 49
Laboratory assessments.............................................................................................................. 49
Blood and urine safety analysis.................................................................................................. 51
Crystalluria................................................................................................................................. 52
Pregnancy testing....................................................................................................................... 52
Measurements of secondary and exploratory variables.......................................................52
Efficacy assessment ................................................................................................................... 52
Pharmacokinetic assessment ...................................................................................................... 53
Biomarkers assessment .............................................................................................................. 53
Quality of life assessment .......................................................................................................... 55
Biobank...................................................................................................................................... 55
STUDY POPULATION ................................................................................................. 55
INCLUSION CRITERIA ................................................................................................................56
EXCLUSION CRITERIA ...............................................................................................................56
WITHDRAWAL OF THE PATIENT ................................................................................................57
STUDY PRODUCTS ..................................................................................................... 58
INVESTIGATIONAL MEDICINAL PRODUCTS ................................................................................59
Dosage and dosage schedule of the investigational medicinal products.............................59
Administration of the investigational medicinal products...................................................59
Supply and storage conditions of the investigational medicinal products...........................59
Packaging and labelling of the investigational medicinal products ....................................60
CONTRAINDICATIONS ...............................................................................................................60
USE OF CONCOMITANT MEDICATIONS.......................................................................................62
COMPLIANCE............................................................................................................................63
ADVERSE EVENTS...................................................................................................... 63
DEFINITION OF AN ADVERSE EVENT..........................................................................................63
DEFINITION OF A TREATMENT EMERGENT ADVERSE EVENT......................................................63
DEFINITION OF A SERIOUS ADVERSE EVENT ..............................................................................63
DEFINITION OF AN ADVERSE EVENT OF SPECIAL INTEREST........................................................64
DEFINITION OF A NEW FACT......................................................................................................64
DEFINITION OF SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTION ...................................64
RECORDING OF AN ADVERSE EVENT .........................................................................................64
REPORTING OF SERIOUS ADVERSE EVENTS AND NEW FACTS .....................................................66
REPORTING OF ADVERSE EVENTS OF SPECIAL INTEREST...........................................................67
CLINICAL EVENTS RELATED TO ALS ........................................................................................67
TREATMENT OF OVERDOSE.......................................................................................................67
STATISTICS ................................................................................................................. 68
STATISTICAL AND ANALYTICAL METHODS................................................................................68
General statistical considerations........................................................................................68
Sample size .........................................................................................................................68
Analysis Sets.......................................................................................................................68
Population and baseline characteristics description ............................................................69
Efficacy / safety analysis.....................................................................................................69
Primary outcome........................................................................................................................ 69
Secondary outcomes .................................................................................................................. 69
ETHICS ......................................................................................................................... 72
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9.1             STATEMENT..............................................................................................................................72
9.2             INDEPENDENT ETHICS COMMITTEE ...........................................................................................72
9.3             INDEPENDENT DATA MONITORING COMMITTEE ........................................................................72
9.4             INFORMED CONSENT.................................................................................................................73
10.             CONTRACT RESEARCH ORGANISATION AND SUBCONTRACTORS ................ 73
11.             SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA / DOCUMENTS ......... 74
12.             QUALITY CONTROL AND QUALITY ASSURANCE................................................ 74
12.1          STUDY MONITORING ................................................................................................................74
12.2          AUDIT.......................................................................................................................................75
13.             CONFIDENTIALITY, DATA HANDLING AND RECORD KEEPING ...................... 75
13.1          CONFIDENTIALITY ....................................................................................................................75
13.2          DATA HANDLING ......................................................................................................................75
13.3          RECORD KEEPING .....................................................................................................................75
13.3.1       Investigator .........................................................................................................................75
13.3.2       Sponsor ...............................................................................................................................76
14.             INSURANCE AND FINANCES .................................................................................... 76
14.1          INSURANCE...............................................................................................................................76
14.2          FINANCES .................................................................................................................................76
14.3          PATIENT PAYMENTS AND EXPENSES..........................................................................................77
15.             REPORT AND PUBLICATION POLICY .................................................................... 77
15.1          REPORT.....................................................................................................................................77
15.2          DISCLOSURE OF DATA...............................................................................................................77
15.3          PUBLICATION............................................................................................................................77
16.             REFERENCE LIST....................................................................................................... 78
17.             APPENDICES................................................................................................................ 81
17.1          SCALES AND QUESTIONNAIRES .................................................................................................81
17.1.1       ALSFRS-R..........................................................................................................................81
17.1.2       ALS-MITOS .......................................................................................................................84
17.1.3       King’s College scale ...........................................................................................................88
17.1.4       ALSAQ-40..........................................................................................................................91
17.1.5       C-SSRS ..............................................................................................................................101
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LIST OF TABLES
Table 1 – Tissues distribution of IFB-088 and guanabenz in rats .................................................................34
Table 2 – Schedule of activities.....................................................................................................................36
Table 3 – Schedule and location of the blood, urinary and cerebrospinal fluid tests.....................................50
Table 4 - Composition of IFB-088 and placebo tablets.................................................................................59
Table 5 - Forbidden concomitant medications ..............................................................................................62
LIST OF FIGURES
Figure 1- Study scheme.................................................................................................................................33
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
µg
µL
µM
ABG
AE
AESI
ALS
ALSAQ-40
ALSFRS-R
ALP
ALT
ANC
ANCOVA
AST
AUC
AUCinf
AUCt
BDNF
b.i.d.
BMI
C9ORF72
CA
CBEU
CDISC
CI
Cmax
COVID-19
CRA
CRO
CSF
08-Apr-2024
Microgram
Microliter
Micromolar
Arterial blood gases
Adverse event
Adverse event of special interest
Amyotrophic lateral sclerosis
ALS assessment questionnaire
Revised ALS functional rating scale
Alkaline phosphatase
Alanine aminotransferase
Absolute Neutrophil Count
Analysis of covariance
Aspartate aminotransferase
Area under the plasma concentration-time curve
Area under the plasma concentration-time curve until
infinity
Area under the plasma concentration-time curve until the
last observation time
Brain-derived neurotrophic factor
Twice a day (bis in die)
Body mass index
Chromosome 9 open reading frame 72
Competent authorities
Cytobacteriological examination of urine
Clinical data interchange standards consortium
Confidence interval
Maximum plasma concentration
Coronavirus disease 2019
Clinical research associate
Clinical research organisation
Cerebrospinal fluid
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CSR
CYP
CONFIDENTIAL
Clinical study report
Cytochrome P450
TRIALS study
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CYP1A2
CYP2C19
CYP2D6
dL
DNA
DRM
DSMB
ECG
eCRF
EDTA
eIF2α
ER
FAS
FTD
FU
FUS
FVC
g
GCP
GGT
GMP
h
HCG
HDL
hERG
HPLC/MS-MS
HTG
ICF
ICH
ICMJE
08-Apr-2024
Cytochrome P450 family 1 subfamily A member 2
Cytochrome P450 family 2 subfamily C member 19
Cytochrome P450 family 2 subfamily D member 6
Decilitre
Deoxyribonucleic acid
Data review meeting
Data and safety monitoring board
Electrocardiogram
Electronic case report form
Ethylenediaminetetraacetic acid
Eukaryotic initiation factor 2α
Endoplasmic reticulum
Full analysis set
Frontotemporal dementia
Follow-up
Fused in sarcoma
Forced vital capacity
Gram
Good clinical practice
Gamma-glutamyl transferase
Good manufacturing practice
Hour
Human chorionic gonadotropin
High-density lipoprotein
Human ether-à-go-go-related gene
High-performance liquid chromatography with tandem
mass spectrometry
Hypertriglyceridaemia
Informed consent form
International Conference on Harmonisation
International committee of medical journal editors
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IEC
IL
IMP
INR
IFNγ
IWRS
kg
KLS
L
LDH
LDL
LLOQ
LP
LPM
LSM
MAD
MAE
MAR
MCP-1
MDAPE
MDPE
MedDRA
miRNA
MITOS
mIU
mg
mL
mmol
MMRM
MPE
mRNA
NfL
ng
CONFIDENTIAL
Independent ethics committee
Interleukin
Investigational medicinal product
International Normalized Ratio
Interferon γ
Interactive web response system
Kilogram
Keyrus Life Science
Litre
Lactate dehydrogenase
Low-density lipoprotein
Lower limit of quantification
Lumbar Puncture
Laboratory procedures manual
Least square means
Multiple ascending dose
Mean absolute error
Missing at random
Monocyte chemoattractant protein-1
Median absolute prediction error
Median prediction error
Medical dictionary for regulatory activities
microRNA
Milano-Torino staging system
Milli-international units
Milligram
Millilitre
Millimole
Mixed model for repeated measures
Mean prediction error
Messenger RNA
Neurofilament
Nanogram
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NGF
nM
NOAEL
NTEAE
PD
PE
pH
PK
popPK
CONFIDENTIAL
Nerve growth factor
Nanomolar
No observed adverse effect level
Non-treatment emergent adverse event
Pharmacodynamics
Prediction error
Potential of hydrogen
Pharmacokinetics
Population pharmacokinetics
TRIALS study
InFlectis BioScience
PPP1R15A/PP1c
PPS
QA
QoL
RNA
SAD
SAP
SD
SO
SmPC
SOD1
SS
SUSAR
SVC
T1/2
TARDBP
TDP-43
TEAE
Tmax
TMF
TNFα
TRICALS
ULN
08-Apr-2024
Protein phosphatase 1 regulatory subunit 15A/protein
phosphatase 1c
Per protocol set
Quality assurance
Quality of life
Ribonucleic acid
Single ascending dose
Statistical analysis plan
Standard deviation
Safety officer
Summary of Product Characteristics
Superoxide dismutase 1
Safety set
Suspected unexpected serious adverse reaction
Slow vital capacity
Half-life
TAR DNA binding protein
TAR DNA-binding protein 43
Treatment emergent adverse event
Time corresponding to Cmax
Trial master file
Tumour necrosis factor α
Treatment research initiative to cure ALS
Upper Limit of Normal
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UPR
V
VEGF
WHO
WOCBP
CONFIDENTIAL
Unfolded protein response
Visit
Vascular endothelial growth factor
World health organisation
Women of childbearing potential
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08-Apr-2024
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1.
INTRODUCTION
1.1
BACKGROUND
1.1.1
Amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis (ALS) is an adult-onset progressive, fatal, neurodegenerative
disorder that results in the gradual degeneration of the motor neurons in the motor cortex
and spinal cord. ALS is the most common type of motor neuron disease with an incidence
rate of 2.8 per 100,000 persons/year and a mean prevalence rate of 5.4 per 100,000 people
in Europe [1]. This disease predominantly affects males, with a male/female incidence rate
ratio of 1.4, and people in their late adulthood, with median age at diagnosis of 65.2 years
for men and 67.0 years for women [2]. Clinical diagnosis of ALS is often a prolonged
process due to heterogeneity in patient presentation and prognosis as well as a lack of robust
diagnostic biomarker [3]. ALS is characterised by rapidly progressive paralysis and death
typically occurs from respiratory failure within 2 to 4 years of symptom onset, although
about 10% of ALS patients manifest a slow form of the disease with a survival of 10 years
or longer [4]. Although the primary symptoms of ALS are associated with motor
dysfunction, up to 50% of patients develop cognitive and/or behavioural impairment during
the course of disease, and 13% of them may present with concomitant behavioural variant
frontotemporal dementia (FTD) [5]. Cognitive and/or behavioural symptoms in patients
with ALS significantly relate to the involvement of bulbar regions affecting speech and
swallowing [6].
There is no curative treatment for ALS. Treatment and therapy options aim at slowing
down the progression of symptoms, preventing complications and improving quality of life
(QoL). Riluzole, the only approved medication in Europe, slows the rate of progression
and prolongs median survival in patients with ALS by 2 to 3 months and despite its
marginal benefits it represents the current standard of care [7]. In Asia, North America and
Switzerland an antioxidant which slows the loss of physical function, edaravone, is also
approved for the treatment of ALS [8].
Depending on the anatomic location firstly affected by the neuropathology, ALS can be
divided into 2 main phenotypes:
·
Limb onset, which begins with weakness in the limbs represents about two-thirds
of all cases. The median survival from symptoms onset is 39 months for lower limb
onset and 27 for upper limb onset [9],
·
Bulbar-onset, in which the muscles of speech, mastication and swallowing are first
affected, accounts for about a third of ALS cases [4]. The bulbar-onset form has
generally a more rapid evolution and a worse prognosis than the limb-onset one,
and is often associated with emotional lability. The median survival from symptom
onset is 25 months [9].
About 10% of ALS is classified as familial, whereas the remaining 90% of cases are
considered sporadic. The genetic aetiology is known only for two thirds of familial cases
and about 11% of sporadic ALS cases. Among the genes identified to be involved in ALS,
there are genes that encode proteins involved in pathways of protein production, trafficking
and degradation. The 4 genes most often found mutated are chromosome 9 open reading
frame 72 (C9ORF72), superoxide dismutase 1 (SOD1), TAR DNA binding protein
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(TARDBP), and fused in sarcoma (FUS) [10]. A specific pathological hallmark of ALS is
the presence of 2 representative cytoplasmic inclusions, Bunina bodies and TAR DNA-
binding protein 43 (TDP-43)-positive cytoplasmic inclusions in degenerating motor
neurons and surrounding glial cells [11]. However, neuronal susceptibility to ALS is not
only confined to motor neurons [12]. It has been suggested that pathological processes
underlying ALS begin in motor neurons and propagate to other regions of the brain in a
fashion that is predictable based on proximity and connection by a corticofugal axonal
spread, consistently with the inclusion and dissemination of TDP-43 pathology [13, 14].
Growing evidence suggests that an impairment of proteome homeostasis is responsible for
the cytoplasmic presence of ubiquitylated protein inclusions and for ALS pathogenesis [15,
16]. One evidence of the proteome homeostasis impairment is the endoplasmic reticulum
(ER) stress and the activation of unfolded protein response (UPR) signalling pathways
demonstrated in motor neurons of in vitro and in vivo models of ALS [17, 18] as well as in
human post-mortem tissues from patients with a familial or sporadic form of ALS [19-21].
Targeting components of the UPR pathway and consequently modulating the proteostatic
capacity of motor neurons is considered a powerful tool to delay the symptomatic phase of
ALS [16]. The phosphatase complex protein phosphatase 1 regulatory subunit 15A/protein
phosphatase 1c (PPP1R15A/PP1c) has been one of these targets. The prolongation of
protein translation attenuation by PPP1R15A/PP1c phosphatase complex inhibition could
be beneficial to decrease the build-up of misfolded proteins in the ER and favour the cells
survival. This activity was first shown with guanabenz, an α2 adrenergic receptor agonist
[22]. Several preclinical studies have shown that guanabenz improves misfolded protein
clearance, reducing ER stress and neuronal death and prolonging the survival in in vitro
and in vivo models of ALS [23-25]. These positive data have been confirmed in the
ProMISe phase II clinical study [26] where 201 patients were randomised to receive
guanabenz 64 mg, 32 mg, 16 mg, or placebo as an add-on therapy to riluzole for 6 months.
Guanabenz at 32 mg or 64 mg administered together with riluzole reduced the proportion
of patients progressing to higher stages of disease in 6 months as measured by the ALS
Milano-Torino staging score (ALS-MITOS) and decreased the decline rate in the revised
ALS functional rating scale (ALSFRS-R) total score. The benefits were more pronounced
in patients with bulbar-onset ALS. However, because of its α2 adrenergic activity,
guanabenz also has a hypotensive effect. Due to this effect, the proportion of patients who
experienced at least one adverse event (AE) was higher in any guanabenz arm than in the
placebo arm leading to a higher drop-out rate, which discouraged further development in
ALS. A selective inhibitor of PPP1R15A/PP1c phosphatase complex devoid of α2
adrenergic activity and consequent side-effect profile represents a promising therapeutic
approach for ALS patients.
1.1.2
IFB-088
The small synthetic molecule IFB-088, also referred to as icerguastat or Sephin1, is a
selective inhibitor of PPP1R15A/PP1c phosphatase complex developed by InFlectis
BioScience. A medicinal chemistry program based on selective optimisation of side
activity was developed to design guanabenz analogues that would be devoid of agonist α2
adrenergic activity but would retain its cytoprotective effect; this has allowed the
identification of IFB-088 [27]. Similarly to guanabenz, IFB-088 is intended to prolong the
UPR as a way to protect the cell against toxic effects of cellular stress. In stress conditions,
the inhibition of PPP1R15A/PP1c phosphatase complex by IFB-088 increases the
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phosphorylation of eukaryotic initiation factor 2α (eIF2α), which in turn leads to the
prolongation of protein translation attenuation. This decrease in protein synthesis
attenuates the ER stress and therefore causes a reduction in the activation of phosphorylated
eIF2α downstream pathway, helping with ER stress resolution. Ultimately, the reduction
of ER stress by IFB-088 allows the survival of the cell against ER stress and reduces
consequent cell death (IFB-report: IFB_R_009_v2).
Preclinical studies
The efficacy of IFB-088 was evaluated in vitro and in vivo in models relevant for ALS. In
TDP-43-overexpressing human bone osteosarcoma epithelial cells, IFB-088 at 50 μM
reduced the number of TDP-43-positive cytoplasmic inclusions without impacting TDP-
43 localisation in the nucleus. In combination with riluzole 5 µM, IFB-088 from 5.5 µM to
50 µM reduced the number of TDP-43 stress granules in the cytoplasm (Report Inflectis
21-S30710; Report 29102021). In rat primary spinal motor neurons injured with glutamate,
an in vitro excitotoxicity assay, IFB-088 at 100 nM and 500 nM reduced the cytoplasmic
TDP-43 mislocalisation similarly to what was observed for riluzole 5 μM. The
coadministration of IFB-088 with riluzole did not lower the protective effect of riluzole
(Report IIS21.01).
In a mouse model of ALS using mice overexpressing the superoxide dismutase 1
containing the mutation G93A (SOD1 G93A), IFB-088 orally administrated at 1 mg/kg
twice a day or at 5 mg/kg once a day, was shown to respectively partially and almost
completely prevent the motor deficit associated with motor neurons loss in these mice.
Moreover, IFB-088 prevented the accumulation of insoluble SOD1 mutant and decreased
ER stress markers in SOD1 G93A spinal cords [27].
Based on in vitro and in vivo data in rats and dogs, the primary metabolic pathway of IFB-
088 was oxidation by cytochrome P450 (CYP) family 1 subfamily A member 2 (CYP1A2)
and subsequent glucuronidation. The main metabolite of the oxidation process was named
IFB-139, which was demonstrated to be pharmacologically inactive. CYP family 2
subfamily D member 6 (CYP2D6) and CYP family 2 subfamily C member 19 (CYP2C19)
could also contribute to the metabolism of IFB-088, albeit to a much lower extent.
To support the safety of repeated-dose oral administration in humans, IFB-088 was
assessed in a series of nonclinical studies that included safety pharmacology, general
toxicology, genetic toxicology and embryofetal developmental toxicity studies.
Safety pharmacology studies
No causes of concerns were reported in the safety pharmacology program (in vitro
selectivity tests against 44 potential off-targets, in vitro study for effects on the human ether-
à-go-go-related gene [hERG] channel and in vivo studies for effects on cardiovascular
function in Beagle dogs and on the central nervous system and respiratory function in
Sprague-Dawley rats).
General toxicology studies
The toxicity profile of repeated oral administration of IFB-088, in a twice daily regimen,
was fully characterised in one rodent (Sprague Dawley rat) and one non-rodent (Beagle
dog) species up to 26 weeks and 39 weeks, respectively. The primary and dose-limiting
effects in repeated-dose toxicity studies in rats were crystal nephropathy and associated
secondary changes at doses above 3 mg/kg/day. Therefore, the no observed adverse effect
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level (NOAEL) in this species was set at 1.5 mg/kg/twice a day [b.i.d.], i.e. 3 mg/kg/day.
No signs of crystal nephropathy were however reported in dogs and rabbits (embryofoetal
development study) at dose levels of up to 16 mg/kg/day (8 mg/kg/b.i.d.) and 24 mg/kg/day
(12 mg/kg b.i.d), respectively. Based on the toxicity data gathered in the 4-week toxicity
study in rats, it was hypothesised that the toxicity was more related to the maximal
concentration (Cmax) than to the area under the curve (AUC); therefore, IFB-088 schedule
of administration was changed from once daily administration to twice daily administration
for all subsequent studies, in order to minimize peak plasma concentrations and keep
targeted plasma exposures. The twice daily schedule of administration was used during
phase I P188 Study and is intended to be used for all the upcoming clinical trials.
Genotoxicity studies
The genotoxicity of IFB-088 was evaluated in in vitro and in vivo studies. In the in vitro
Ames test a weak and equivocal increase in mutant frequency was observed in the presence
of metabolic activation on one out of the 5 tested strains. No genotoxic effect was observed
in the in vitro study to assess the potential to induce chromosome aberrations in cultured
human peripheral blood lymphocytes. The in vivo study was performed on Sprague-
Dawley rats combining a micronucleus test in the bone marrow tissue and a Comet assay
in the liver. Animals were treated orally once a day for 3 consecutive days, 24 hours apart,
at dose levels of 0, 5, 10 and 20 mg/kg/day. Both endpoints showed no evidence of
genotoxicity. Based on these results, IFB-088 is anticipated to have no genotoxic hazard to
humans.
Reproductive toxicity studies
Reproductive toxicity potential of IFB-088 was assessed in one study for effects on fertility
and general reproductive performance in Sprague Dawley rats, and 2 studies for effects on
embryofoetal development in Sprague Dawley rats and New Zealand white rabbits.
In the fertility and general reproductive performance study in male and female Sprague
Dawley rats (at IFB-088 doses of 1.5, 3 or 6 mg/kg b.i.d., i.e. 3, 6 or 12 mg/kg/day), an
impact on reproductive parameters (prolonged oestrus cycle, decreased number of corpora
lutea and implantation sites), associated with evidence of parental toxicity comparable to
that observed in the repeated-dose toxicology studies (clinical signs, decreased food
consumption and body weight and evidence of kidney damage), were reported at the dose
of 12 mg/kg/day. No treatment-related effects on parental and reproductive parameters
were observed at the doses of 3 and 6 mg/kg/day (NOAEL was thus established at 3
mg/kg/b.i.d).
In the embryofoetal development study in female Sprague Dawley rats (IFB-088 doses of
1.5, 3 or 6 mg/kg b.i.d., i.e. 3, 6 or 12 mg/kg/day), skeletal malformations, associated with
evidence of maternal toxicity (clinical signs, decreased appetite and body weight, signs of
renal toxicity), were observed in some foetuses at doses of 6 and 12 mg/kg/day. The
NOAELs for maternal parameters and for embryofoetal development were considered to
be 1.5 mg/kg b.i.d.
In the embryofetal development study in female New Zealand White rabbits, there was no
evidence of test item related effects on maternal parameters or on hysterectomy data up the
highest administered dose of 24 mg/kg/day. Therefore, 12 mg/kg b.i.d. was concluded to
be the NOAELs for maternal parameters and for embryofetal development.
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At this stage of IFB-088 development, the pre- and post-natal developmental toxicity study
in laboratory animals is not required. Therefore, women who are pregnant or lactating will
be excluded from this trial. According to the preclinical tests results, the risk assessment
for IFB-088 resulted in possible human teratogenicity/foetotoxicity in early pregnancy.
Women with childbearing potential will be asked to take contraceptive measures according
to this evaluation.
Clinical studies
Phase I study P188 (NCT03610334, EudraCT 2018-000443-29) was a randomised, double-
blind, placebo-controlled, single and multiple ascending dose study to evaluate the safety,
tolerability and pharmacokinetics (PK) of IFB-088 when administered to healthy adult
subjects. The study consisted of a single ascending dose (SAD) part, and a multiple
ascending dose (MAD) part. The study is complete and a total of 72 subjects received
IFB-088 or placebo. In the SAD part, 36 subjects received single daily doses of IFB-088
ranging from 2.5 to 60 mg; in the MAD part, 18 subjects received multiple doses of IFB-
088 ranging from 15 mg to 50 mg over 14 days. Drug absorption was rapid and maximum
concentrations were observed at approximately 1-2 hours (median time at which the Cmax is
observed [Tmax]) following single and multiple oral dose administration of IFB-088. Dose
proportionality was observed for IFB-088 Cmax and AUC following single daily doses of
10 to 60 mg and multiple daily doses of 15 to 50 mg for 14 days. IFB-088 half-life was 4.6
to 6.2 hours following single doses and 5.7 to 8.4 hours following multiple dosing. The
terminal elimination half-lives were similar between Days 1 and 14, suggesting the
stationarity (time-independence) of the IFB-088 PK over 14 days. Following repeated bi-
daily administration, the drug accumulation ratio ranged between 1.4 and 1.6. Very low
concentrations of IFB-088 were evident in urine; the percentage of the administered dose
excreted unchanged in urine was < 1%. The primary metabolic pathway proposed in
nonclinical studies included the oxidation of IFB-088 to IFB-139 (phase I metabolite)
followed by glucuronidation (phase II metabolite), and was confirmed in the P188 study.
Based on the population PK model, renal clearance likely marginally contributes to IFB-
088 total clearance, while the formation of metabolite IFB-139 by hydroxylation has a
major contribution to IFB-088 elimination.
In terms of safety, IFB-088 was well tolerated in healthy subjects at all doses evaluated,
including single daily doses up to 60 mg and repeated doses up to 50 mg daily for 14 days.
No deaths, serious AEs (SAEs) or severe drug-related treatment emergent AEs occurred
during the study. No AEs led to study discontinuation, discontinuation of dosing, or
discontinuation of dose escalation. There was no relationship between IFB-088 or placebo
treatment and the frequency or nature of treatment emergent AEs (TEAEs). There was also
no relationship between increasing dose and the frequency or type of TEAEs.
1.2
RATIONALE FOR THE STUDY
The pathological hallmark of ALS is the presence of ubiquitin-positive inclusions
consisting of misfolded protein aggregates in the affected motor neurons and glial cells of
the spinal cord and motor cortex, suggesting that the proteome homeostasis is impaired in
ALS [11, 15, 16]. One evidence of the proteome homeostasis impairment is the ER stress
and the activation of UPR signalling pathways in human post-mortem tissues from patients
with familial or sporadic form of ALS. In addition, biochemical and morphological
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findings correlate the development of ALS with the markers of ER stress and the activation
of UPR pathway [19, 21].
Targeting the UPR pathway, in particular the phosphatase complex PPP1R15A/PP1c could
be beneficial to ALS patients. Encouraging results were obtained with guanabenz in an
exploratory phase II study in ALS patients, especially in patients with the bulbar onset of
ALS. IFB-088 has demonstrated activity in the so far best studied animal model of ALS,
i.e. transgenic rodents overexpressing the gene encoding SOD-1 [27]. Moreover, IFB-088
is devoid of α2 adrenergic activity, which is responsible for the hypotensive effect of
guanabenz, despite maintaining its effect on UPR. The clinical development program of
IFB-088 to date has shown no particular safety concerns at all doses evaluated, including
single daily doses up to 60 mg/day and repeated doses up to 50 mg daily for 14 days. Since
a similar efficiency to guanabenz is expected from IFB-088 without hypotensive effects,
an exploratory phase II study has been designed to assess the safety and the efficacy of
IFB-088 as an add-on to the standard of care riluzole in patients with bulbar onset of ALS.
Bulbar-onset ALS population was selected to be the target of this study as the benefit of
guanabenz was higher and primarily observed in bulbar-onset ALS patients compared to
limb-onset ALS patients [26].
Based on the results of preclinical toxicity studies, IFB-088 will be administered twice a
day in order to minimize peak plasma concentrations and keep targeted plasma exposures.
The dosage of 50 mg/day has been selected based on the results obtained with guanabenz
in the ProMISe phase II clinical trial [26] (see Section 3.3). Patients will be treated during
6 months. This duration is considered acceptable in view of the exploratory aim of the
study.
1.3
BENEFIT-RISK ASSESSMENT
To date, therapeutic options for ALS are still very limited and no curative treatment exists.
Riluzole, the only approved medication in Europe, improves survival in ALS patients by 2
or 3 months only. Although relatively well tolerated, it can cause hepatotoxicity [28]. Apart
from riluzole, treatment of ALS is mainly palliative. Considering the seriousness of the
disease and the limited options for treatment, there is still a high unmet medical need for
patients suffering from ALS.
In the ProMISe phase II clinical study [26], guanabenz at 64 mg and 32 mg significantly
reduced the proportion of patients progressing to higher stages of disease compared to what
was expected under the hypothesis of non-futility, as measured by the ALS-MITOS.
Moreover, a slowing down in the decline rate of daily living activities was recorded as
measured by ALSFRS-R total score. The benefits were more pronounced in patients with
bulbar-onset ALS.
Thus, the ProMISe study confirmed that controlling the UPR pathway may be of benefit in
slowing the progression of ALS. However, the hypotensive effect of guanabenz linked to
its α2 adrenergic receptor activity represented a limit to its practical application, and further
clinical development was interrupted.
IFB-088, developed by InFlectis Bioscience is a close analogue of guanabenz devoid of
agonist α2 adrenergic activity. Therefore, it is expected to have similar efficacy compared
to guanabenz, without hypotensive adverse effects. In the phase I first-in-human study
P188 (NCT03610334), IFB-088 was well tolerated at all doses evaluated, including single
daily doses up to 60 mg and repeated doses up to 50 mg daily for 14 days.
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The safety results from the phase I study are reassuring and no serious adverse reactions
are considered expected by the sponsor for the purpose of expedited reporting of suspected
unexpected serious adverse reactions (SUSARs). However, human safety data with
IFB-088 are limited to the results of this first-in-human study on healthy volunteers. Since
IFB-088 has never yet been tested in ALS patients, who may present with potential
additional risk factors linked to their condition, a set of measures will be implemented in
this study in order to minimise those potential risks, including i) Restriction of eligibility
criteria to patients with no other serious illness(es) or medical condition(s) such as cancer,
cardiac, liver, renal or haematological diseases, ii) Regular monitoring of safety laboratory
and clinical AEs in all patients enrolled in the present clinical trial, since as with any new
drug, there is a risk that unidentified or unexpected side effects may occur, iii) Definition,
monitoring and specific reporting procedure for AEs of special interest (AESIs), iv)
Implementation of a data safety monitoring board (DSMB) for periodic benefit risk
assessment.
In preclinical studies, kidneys appeared to be the only affected organs in Sprague Dawley
rats at IFB-088 doses above the NOAEL (1.5 mg/kg/b.i.d., i.e. 3 mg/kg/day). Adverse,
dose-related crystal nephropathy was observed in both sexes, but at slightly lower doses in
males compared to females and was the first cause of moribundity and death. No signs of
crystal nephropathy were reported in dogs and rabbits at dose levels of up to 16 mg/kg/day
(i.e. 8 mg/kg b.i.d.) and 24 mg/kg/day (i.e. 12 mg/kg b.i.d), respectively. In the phase I
P188 study no changes in the renal-associated biochemistry parameters and no IFB-088
related AEs from the renal system organ class were reported. Although the renal findings
in the Sprague Dawley rat strain are not completely understood yet, the current data suggest
that it likely represents a species-specific toxicity not representative of the risk in humans.
Nonetheless renal toxicities will be reported in this study as AESIs and renal function will
be closely monitored, along with microscopic examination of urine to detect crystals.
Definitive pre- and post-natal developmental toxicity studies with IFB-088 have not been
conducted. For this reason, the use of IFB-088 is contraindicated in women who are
pregnant or lactating and precautions will be used in women of childbearing potential.
Based on the preclinical and phase I safety results, the risk associated to the administration
of IFB-088 is considered to be acceptable for ALS patients, particularly in view of a
possible beneficial effect in slowing down the progression of the disease and in improving
the daily living functionality, as demonstrated for guanabenz. An efficacy comparable to
that of guanabenz at corresponding doses is expected. This clinical trial is an exploratory
study, designed to confirm the results of guanabenz in ALS patients with the aim of
assessing the safety and providing proof of efficacy of IFB-088.
Overall, considering the poor prognosis of ALS patients, the urgent need for developing
more efficacious ALS therapeutic alternatives, the promising efficacy results from
guanabenz phase II study and the reassuring safety results of the IFB-088 phase I study,
the potential benefits expected for IFB-088 outweigh the known and potential risks of IFB-
088 administration in patients with bulbar-onset ALS during a phase II exploratory study.
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2.
STUDY OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
To assess the safety of the test product,
IFB-088 50 mg/day, in patients with
bulbar-onset ALS.
Secondary and exploratory
To assess the efficacy of IFB-088 50
mg/day plus riluzole 100 mg/day versus
placebo plus riluzole 100 mg/day over a 6-
month period in patients with bulbar-onset
ALS.
·
Incidence, grade and relationship to
IFB-088 for treatment emergent
AEs, SAEs, and AESIs,
·
 AEs leading to dose interruption or
premature discontinuation.
·     Change in ALSFRS-R score from
baseline to month 3 and to month 6,
·
Worsening according to ALS-
MITOS score, i.e. progression to a
higher stage at 3 and at 6 months
compared to the baseline,
·
Change in King’s College score
from baseline to month 3 and to
month 6.
Exploratory endpoints:
·
Assessment of respiratory function
(slow vital capacity [SVC], sniff
test [optional], arterial blood gases
[ABG]).
·
Evaluation of nutritional status and
body composition by bioelectrical
impedance.
To determine the PK parameters of IFB-
088.
Measurements of PK parameters:
·
Plasma concentration of IFB-088
and IFB-139,
·
AUC of IFB-088 and IFB-139,
·
Maximum
observed
plasma
concentration         (Cmax),         with
associated Tmax,
·
Terminal or apparent terminal half-
life (t1/2),
·
Apparent
systemic
clearance,
apparent volume of distribution.
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To investigate the effects of IFB-088 on
potential biomarkers.
·
Change
in
TDP-43
plasmatic
concentration from baseline to 6
months, compared to placebo,
·
Change in neurofilament (NfL)
light chain and NfL heavy chain
plasmatic
concentration
from
baseline to 6 months, compared to
placebo,
·
 Change
in
plasmatic
(neuro)inflammatory     biomarkers
from baseline to 3 months, and
from
baseline     to     6     months,
compared to placebo,
·
Change in plasmatic oxidative
stress biomarkers from baseline to
3 months and from baseline to 6
months, compared to placebo.
To investigate the QoL of ALS patients.
Change in ALS assessment questionnaire
(ALSAQ-40) from baseline to 6 months.
3.
STUDY DESIGN
3.1
STUDY DESIGN OVERVIEW
This is a prospective, international, randomised, double-blind, placebo controlled, and
multicentre, parallel group phase II study. Patients with bulbar-onset ALS will be recruited
in University hospitals in France and Italy. Patients will be randomised in a 2:1 allocation
ratio to receive either IFB-088 50 mg/day + riluzole 100 mg/day or placebo + riluzole 100
mg/day.
Patients will be treated for a period of 6 months (26 weeks). Only patients who have
consented and meet the inclusion and exclusion criteria will be eligible for participation in
the study.
Patients will undergo 8 visits, as illustrated in Figure 1: screening visit (within 2 weeks
before V0), baseline visit (V0), visit 1 (V1, 2 weeks ± 3 days after V0), visit 2 (V2, 4 weeks
± 4 days after V0), visit 3 (V3, 9 weeks ± 4 days after V2), visit 3bis (V3bis, 6.5 weeks ±
4 days after V3), visit 4 (V4, 13 weeks ± 4 days after V3), and a follow-up (FU) visit (V-
FU, 4 weeks ± 1 week after V4). In addition to these hospital visits, patients will undergo
urine analysis (dipstick) and blood sampling for measurement of creatinine one week after
V0, as well as blood sampling for measurement of creatinine and calculation of eGFR at
months 2, 4 and 5; these exams can be done in any laboratory, depending on the patient's
choice. In case of premature study discontinuation, a final visit (premature discontinuation
visit) will take place as soon as possible and no later than 4 weeks after the last
investigational medicinal product (IMP) intake. A detailed list of procedures performed at
each visit is presented in Sections 3.7 and 4.
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During the screening visit, patient eligibility will be assessed. Patients will be randomised
at the baseline (V0) visit after confirmation of eligibility. Safety will be monitored over all
the course of the study by a DSMB.
The study will be submitted for approval to the independent ethics committees (IECs) and
signed informed consent will be obtained from all patients before any study procedures are
conducted.
Compliance with coronavirus disease 2019 (COVID-19)-related rules will be followed and
adjustments might be necessary accordingly. In particular, if hospital visits must be limited
due to governmental or local hospitals' decisions, or for practical reasons due to insufficient
resources in healthcare professionals, the V1 visit (2 weeks after V0), could be replaced by
laboratory assays performed in a local lab (for which the patient would receive a written
prescription), and a phone call to investigate for any symptom evocative of adverse event.
Unless they already obtained treatment research initiative to cure ALS (TRICALS)
certificates, study examiners will undergo online training to ensure uniformity of study
procedures across sites, and inter-rater variability will be documented. For investigators
who cannot undergo the TRICALS training, certification from the Barrow Neurological
Institute is acceptable. Management of frailty will be performed according to standard of
care, under the responsibility of each site's investigator.
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Figure 1- Study scheme
* Urine analysis and blood sampling will be additionally performed one week after V0.
** Blood sampling for measurement of creatinine and calculation of eGFR will be additionally performed
at 2, 4 and 5 months.
IMP: investigational medicinal product, V: visit, FU: follow-up.
3.2
RATIONALE FOR THE STUDY DESIGN
To assess the effects of medicinal products for treatment of ALS, parallel, double-blind,
randomised placebo-controlled trials are optimal. Riluzole is the only available drug in
Europe for the treatment of ALS and despite its limited effect in reducing the disease
progression, it is the current standard of care. Therefore, for ethical reasons, as IFB-088
has not yet demonstrated efficacy in this indication, it will be administered as an add-on
treatment in combination with riluzole. Patients will be randomised to receive either the
new drug or the placebo; the trial objectives will be to assess the safety of IFB-088 in
patients with bulbar-onset of ALS and to show a signal of efficacy.
3.3
DOSE JUSTIFICATION
The 50 mg/day dose of IFB-088 selected for this study is based on the results obtained with
guanabenz combined to riluzole 100 mg/day in the ProMISe trial [26]. In the ProMISe
study, the intermediate dose (16 mg twice a day; 32 mg/day) and high dose (32 mg twice a
day; 64 mg/day) of guanabenz showed efficacy in patients with bulbar-onset ALS as
reflected by a statistically significant decrease in the percentage of patients who progressed
to a higher ALS-MITOS score after 6 months (primary endpoint). The rate of ALSFRS-R
decline was also significantly lower in the guanabenz high and intermediate doses arms
compared to placebo and guanabenz low dose arms.
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Guanabenz and IFB-088, both targeting the PPP1R15A/PP1c phosphatase complex, have
similar pharmacological activity in vitro (results from preclinical studies on cytoprotective
effect on ER stress: reports IFB_R_009_V2, and on TDP-43 cytoplasmic stress granule
reduction: Inflectis 21-S30710 and 29102021). Furthermore, these compounds, which
differ only by one chlorine atom, have similar metabolic pathways and the exposure to
IFB-088 in tissues of interest (central and peripheral nervous system) is at least as high as
that of guanabenz in rats (report 16-326, see Table 1).
Table 1 – Tissues distribution of IFB-088 and guanabenz in rats
Cmax (ng/mL for plasma
AUCt (ng/mL*h for
AUCinf (ng/mL*h for
T1/2 (h)
and ng/g for tissues)          plasma and ng/g*h for        plasma and ng/g*h for
tissues)
tissues)
IFB-088 (3 mg/kg)
Plasma
17.4
12.5
22.8
2.98
Brain
31.2                                      192.6                                       NC
Sciatic nerve
751.3
5674.9
5717
Guanabenz (3 mg/kg)
Plasma
47.2
19.74
21.0
2.29
Brain
18.8                                       70.2                                        NC
Sciatic nerve
1108
2874.6
NC
Cmax: maximum plasma concentration, AUCt: area under the plasma concentration-time curve until the last
observation time, AUCinf: area under the plasma concentration-time curve until infinity, ng: nanogram, mg:
milligram, mL: milliliter, g: gram, kg: kilogram, h: hour, T1/2: half-life, NC: not calculated.
The molecular weights of free bases of guanabenz and IFB-088 are 231.08 g/mol and
196.64 g/mol respectively, leading to a guanabenz: IFB-088 molecular weight ratio of 1.18.
Hence, IFB-088 doses corresponding to the intermediate and high doses of guanabenz in
the ProMISe trial are:
Intermediate dose: 2 x 16 mg of guanabenz corresponding to 2 x 13.6 mg of IFB-088
High dose: 2 x 32 mg of guanabenz corresponding to 2 x 27.1 mg of IFB-088
IFB-088 is therefore anticipated to be efficient in the range of 2 x 13.6 mg/day
(27.2 mg/day) to 2 x 27.1 mg/day (54.2 mg/day).
This clinical trial is an exploratory study, designed to confirm the results of guanabenz in
ALS patients, therefore, to show a signal of efficacy of IFB-088. It will not investigate any
dose effect relationship: only one dose of IFB-088 will be tested. In order to maximise the
probability of showing efficacy, it has been decided to select the dose corresponding to the
higher end of the targeted range. As 50 mg/day (25 mg twice a day), the highest dose tested
in the MAD part of the phase I study, was safe and well tolerated, this dose will be used in
the phase II study.
3.4
STUDY DURATION
The overall study duration will be approximately 2 years and 6 months. The IMPs will be
administered for 6 months (26 weeks) and each patient will undergo 8 visits over a period
of about 7 months (32 weeks maximum). The V-FU will take place 4 weeks ± one week
after V4.
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3.5
STUDY COMPLETION AND FOLLOW-UP
A patient is considered to have completed the study if he/she has completed all study visits
and attended the V-FU, which must take place 4 weeks (time window ± one week) after
the V4 visit.
The end of the study is defined as the date of the V-FU for the last subject in the study.
All patients who are prematurely withdrawn from the study will undergo a final assessment
as soon as possible and no later than 4 weeks after the last study drug intake.
3.6
PREMATURE TERMINATION OF THE STUDY
The sponsor reserves the right to temporarily suspend or prematurely discontinue this study
at any time if, in the opinion of the sponsor, the DSMB or the investigator, there is
reasonable cause. Written notification, documenting the reason for study suspension or
termination, will be provided by the suspending or terminating party. The IECs and
pertinent regulatory authorities will be informed according to the national regulations of
the suspension or termination of the study and the reason(s) for this action. Circumstances
that may warrant termination include:
·
Failure to enrol patients,
·
Major protocol violations,
·
Inaccurate or incomplete data,
·
Unsafe or unethical practices,
·
Questionable safety of the study product,
·
Plans to modify, suspend, or discontinue the development of the IMP.
3.7
SCHEDULE OF ACTIVITIES
The scheduling of study procedures is outlined in Table 2 and detailed in Section 4.1.
All data obtained from the assessments listed in the schedule of activities and described in
detail in Section 4.2 must be supported in the patient’s source documentation (e.g. medical
charts or patient notes).
Visit dates should be adhered to as closely as possible. If one visit is postponed or brought
forward, it should not result in the next visit being postponed or brought forward. The next
visit, if at all possible, should adhere to the original time schedule.
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Table 2 – Schedule of activities
Visits
Study Weeks
Informed consent (1)
Inclusion/exclusion criteria
Demographic characteristics
Medical history
Physical examination and vital
signs
Weight / BMI
ECG
Serum/urine chemistry
Serum pregnancy test
Urine pregnancy test⨍
Neuropsychological
assessment
Concomitant medications and
AEs
Crystalluria examination
Randomisation
Study drug delivery
ALSFRS-R
ALS-MITOS
King’s College
C-SSRS evaluation (4)
Bioelectrical Impedance
Analysis
ALSAQ-40
SVC
Sniff test (2)
ABG
Plasma biomarkers
Screening
Within 2
weeks before
V0
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Baseline
V0
0
X
X
X
X*
X*†
X
X
X
Xa
X**
X
X
X
X
X
V1
V2
2
4
± 3 days
± 4 days
X
X
X                     X
X
X
X††
X
X
X
X
X
V3
V3bis
V4
13
19.5
26
± 4 days
± 4 days
± 4 days
X
Xx
X
X                                        X
X                    X                  X
X†††                       Xy                           X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Premature
discontinuation
-
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
V-FU
30
± 1 week
X
X
X
X
X
X
X
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Whole blood biomarkers
X
X
X
Urine biomarkers
X
X
X
International Normalized                                                                                                                                            Xz
Ratio⨍⨍
CSF sampling⨍⨍⨍
X
X
X
Blood samples for PK                                                                                                    X
Administration of study drug
(3)
on site
*Will be performed only if deemed necessary by the investigator.
⨍ In addition to tests mentioned in the table, pregnancy tests will be performed at monthly intervals during treatment and until the end of relevant systemic
exposure.
** Will be performed only if V0 is performed > 15 days after the screening visit.
† A prescription will be given to patients at V0 to perform urine analysis and blood sampling in a local laboratory at V0 + one week.
†† A prescription will be given to patients at V2 to perform blood sampling for creatininemia and eGFR in a local laboratory at V2 + 1 month (i.e., V0 + 2 months).
††† A prescription will be given to patients at V3 to perform blood sampling for creatininemia and eGFR in a local laboratory at V3 + 1 month and V3 + 2 months (i.e.,
V0 + 4 months and 5 months respectively).
⨍⨍ Prior to CSF sampling, only in case CSF sampling is planned.
⨍⨍⨍ Only in patients who accepted to undergo lumbar puncture and do not have contraindications (see section 4.2.2.3).
a: first intake of IMP on site at baseline V0 visit (see section 4.1.2).
x: cardiac auscultation, heart rate, systolic and diastolic blood pressure.
y: selected blood markers, detailed in section 4.1.6.
z: independent of CSF sampling.
(1) Patient will have to sign informed consent form for the study before any study procedure.
(2) Sniff test is optional. It will be performed only in sites that have the equipment and resources to perform this test.
(3) The day before V2 the patient will go on site to be administered the IMP at 20:00.
(4) C-SSRS “Lifetime” version at screening visit. C-SSRS “Since Last Visit” version at V3, V4 and premature discontinuation visits.
BMI: body mass index, ECG: electrocardiogram, AEs: adverse events, ALSFRS-R: revised ALS functional rating scale, ALS-MITOS: ALS Milano-Torino staging,
ALSAQ-40: ALS assessment questionnaire, SVC: slow vital capacity, ABG: arterial blood gases, PK: pharmacokinetics, CSF: cerebrospinal fluid, V: visit, FU: follow-up,
mIU/ml: milli-international units per millilitre.
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3.8
IDENTIFICATION OF PATIENTS
All patients who have signed an informed consent form (ICF) and meet the study
inclusion/exclusion criteria will enter the study by means of an electronic case report form (eCRF).
After eligibility is confirmed, patients will be assigned a number. Patients' numbers will be
allocated in ascending order, the order in which patients are enrolled. The investigator or a staff
member will enter the patient’s number in the eCRF, the confidential patient identification list and
the drug dispensing log. The drug dispensing log will be filled in with the treatment number
without knowing what the treatment is. The confidential patient identification list must contain
sufficient information so that it would be possible to contact the study patient in the event of an
emergency or if any further FU is required.
3.9
RANDOMISATION AND BLINDING
All participants will be centrally randomised in a 2:1 allocation ratio to receive either IFB-088 +
riluzole or placebo + riluzole, respectively. No stratification factor will be taken into account. The
randomisation will be performed through an interactive web response system (IWRS) integrated
into the eCRF. Before the study is initiated, the log in information and directions for the IWRS
will be provided to each site. Investigators will be supplied with user guides for the IWRS. Once
a set of medical characteristics is entered, the IWRS will immediately assign a patient to one of
the 2 arms. After the randomisation visit, the investigator will automatically receive a confirmation
by email with the treatment number allocated to the patient.
This is a double-blinded study. Neither participants, nor investigators, nor trial staff, nor the
sponsor study team will be aware of treatment assignments prior to the database lock at the
conclusion of the study.
3.9.1
Unblinding process
Unblinding before the conclusion of the study can be necessary in the cases detailed in this Section.
Blind break for reasons other than those mentioned in this Section should be first discussed with
the sponsor’s medical monitor.
Unblinding for emergency
In case of an emergency, the investigator has the sole responsibility for determining if unblinding
of a participants’ intervention assignment is necessary for the effective treatment of the patient.
Participant safety must always be the first consideration in making such a determination. However,
the investigator should make all attempts to contact the sponsor’s medical monitor before
proceeding with the unblinding.
The code breaks will be available 24 hours a day and 7 days a week using the IWRS implemented
via the eCRF. The IWRS will require access credentials only available to staff members named on
the delegation log for the trial recorded in the trial master file (TMF) of each site. The investigators
and delegated members with unblinding responsibilities are responsible for testing their credentials
prior to the treatment of patients to ensure unblinding is possible, and for ensuring appropriately
trained staff members are available to action code breaks when required for medical emergencies.
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If a participant’s intervention assignment is unblinded the sponsor must be notified immediately
after breaking the blind even if consultation occurred in advance. Details of any emergency
unblinding must be recorded in the source documentation and eCRF.
This includes, but may not be limited to:
·
Date,
·
Subject details,
·
Reason for unblinding,
·
The results,
·
Name and role of the individual requesting the unblinding,
·
Name and role of the individual carrying out the unblinding.
Following unblinding and appropriate patient's care if needed, the administration of the IMP
should be discontinued and should not be resumed. Subsequent monitoring of patients is however
encouraged, i.e. maintenance of visits as per schedule of activities.
Unblinding for DSMB
If requested, information will be provided to the DSMB unblinded. To that effect, a delegated
person not involved with the final data analysis or with the study, shall receive the relevant codes.
A record shall be kept in the investigator TMF of the name of the statistician, the date they were
supplied the relevant code breaks and the location of the results. The unblinded data and the results
supplied to the DSMB shall not be accessible by the investigators or trial staff.
Unblinding at the end of trial
The statistical analysis plan (SAP) shall be finalised prior to the release of the randomisation codes.
Changes to the SAP should be version-controlled. A record shall be kept in the investigator TMF
to confirm when the randomisation code was requested and when provided.
Unblinding by the pharmacovigilance and safety institution
In case of SUSARs associated with an IMP, the blind needs to be broken by the pharmacovigilance
and safety institution (Stragen) for the purpose of SUSARs processing and reporting. Unblinding
IWRS credentials will be provided to Stragen project manager and his/her backup for this purpose.
4.
STUDY VISITS AND PROCEDURES/ASSESSMENTS
Study procedures and their timing are summarised in the schedule of activities (Section 3.7).
COVID-19 special measures
Specific measures will be put in place according to local regulations as appropriate.
4.1
STUDY VISITS
4.1.1
Screening visit
Prior to any study activities, the patient will be asked to read and sign an ICF that has been
approved by an IEC and which complies with regulatory requirements. Patients will be given
adequate time to consider any information concerning the study given to them by the investigator.
As part of the informed consent procedure, patients will be given the opportunity to ask the
investigator any question regarding potential risks and benefits of a participation in the study.
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Investigators must keep a record (screening log) of patients who were screened. The screening log
must be dated and signed by the investigator and filled into the investigator site file.
The following assessments and investigations will be conducted during this visit:
·
Explanations about the study and signature of ICF. The patient will be able to consent
separately to i) the participation in the study, ii) the storage of biological samples in a
biobank and iii) the collection of cerebrospinal fluid (CSF),
·
Collection of the patient demographic characteristics (date of birth, age, sex, ethnicity),
·
Physical examination and vital signsassessment, according to Sections 4.2.1.2 and 4.2.1.5,
·
Height and weight measurement, and calculation of BMI,
·
12-lead electrocardiogram (ECG) (Section 4.2.1.6),
·
 Blood and urine samples collection for haematology, blood chemistry, and urinary analysis
according to Section 4.2.1.8,
·
 Evaluation of patient eligibility to the study (according to inclusion/exclusion criteria, see
Section 5.1 and 5.2) and documentation in patient’s file:
o Recording of ALS history and diagnosis:
-
ALS diagnosis according to the revised El Escorial criteria [29],
-
Date of first ALS symptom/sign,
-
ALS disease duration from diagnosis to the screening visit,
o SVC assessment,
o ALSFRS-R score measurement and calculation of the ALSFRS-R score progression
rate (point/month) from symptom onset to screening visit,
o Recording of medication history including but not limited to:
-     Riluzole treatment (100 mg/day) and treatment start date,
-
 Concomitant medications and/or non-drug therapies, including the reason for
administration,
-
Knowledge of hypersensitivity to IMPs ingredients,
o Documentation of smoking habits,
o Documentation of the relevant past medical history, any planned surgery and current
medical conditions not related to the diagnosis of ALS,
o Blood pregnancy test in females of childbearing potential,
o Check of contraception methods used by patient (and his/her partner when applicable),
o Neuropsychological assessment (Section 4.2.1.3),
o C-SSRS evaluation,
o Calculation of patient’s weight variation between symptoms onset and screening visit,
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o Check of patient participation in a clinical trial prior to screening and eventual date of
trial termination,
o Check that the patient understands and is able to follow the protocol procedures and is
willing to adhere to the study visit schedule,
·
Sniff test5,
·
ABG,
·
Appointment for the next visit,
·
eCRF recording of data collected.
Screen Failure
A patient who has given his/her consent is considered as a screen failure if:
·
He/she does not meet all the inclusion criteria or meets a non-inclusion criterion,
·
He/she was withdrawn from the study prior to randomisation and study drug intake.
For patients considered as screen failure the following eCRF pages must be completed:
·
Screening visit applicable pages (all performed assessments),
·
Baseline visit pages if applicable (all performed assessments and randomisation/inclusion
decision).
4.1.2
Baseline – V0 visit
The baseline visit (V0) will occur 2 days to 2 weeks after the screening visit.
The following assessments will be conducted before the randomisation:
·
Confirmation of patient eligibility to the study (as in screening visit, see Section 4.1.1),
·
Delivery of patient card,
·
Physical examination and vital signsassessment, according to Sections 4.2.1.2 and 4.2.1.5,
·
Weight and calculation of BMI,
·
Query for changes in concomitant medications,
·
 Ensure that the patient is still willing to follow the protocol procedures and the visits
schedule,
·     Urine pregnancy test in females of childbearing potential (WOCBP)6. In addition to tests
performed at hospital visits, pregnancy tests will be performed at monthly intervals during
5 The sniff test is optional. It will be performed only in sites that have the equipment and resources to perform this
test.
6 High sensitivity urine pregnancy test must be used (sensitivity 25 mIU/ml or more).
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treatment and until the end of relevant systemic exposure. If a positive result is detected
with urine pregnancy test, a serum pregnancy test will be performed to confirm the results.
·
12-lead ECG (Section 4.2.1.6), blood and urine samples collection for haematology, blood
chemistry, and urinary analysis according to Section 4.2.1.8, will not be repeated unless
any intercurrent event might have modified eligibility criteria,
Once patient eligibility is confirmed:
·
Recording of AEs (if any),
·
Randomisation and treatment allocation,
·
Dispensation of study product to the patient,
·
Patients will be given a prescription for urine analysis (dipstick for quantification of blood,
leukocytes, pH, glucose, and proteinuria) and blood sampling (creatininemia) to be
performed at V0 + one week in a local laboratory. Analyses will be performed according
to Section 4.2.1.8. Results of these analyses will be sent to the site in real time.
·
Instructions to the patient:
- Study product must be taken at approximately the same time each morning and each
evening, about 12 hours apart, with a glass of water and 30 minutes before the meal, in
fasting condition. For patients who have swallowing difficulties, tablets can be taken
with a spoon filled with jellified water. The patient will take the first tablet at the V0
visit under a healthcare professional supervision. If this first intake is in the morning,
the patient will take his next dose in the evening at home. If the first intake is in the
afternoon, the patient will take the next dose at home the next morning. From the second
intake, intervals for dosing should ideally be about 12 hours (± 1 hour).
- Study drug must be kept in the original container, at room temperature,
- Daily dose of riluzole must be taken at approximately the same time each morning and
each evening, together with the study product,
- Both used and unused study drug bottles must be returned at the next visit for treatment
accountability,
- The patient will be encouraged to stay well hydrated throughout the duration of the
study.
·
ALSFRS-R measurement if V0 is performed > 15 days after screening visit,
·
ALS-MITOS measurement,
·
King’s College score measurement,
·
Bioelectrical Impedance Analysis
·
Patient’s completion of ALSAQ-40,
·
International Normalized Ratio (INR) if CSF sampling is planned,
·
 Collection of blood, urine and CSF samples for biomarkers analysis according to Section
4.2.2.3,
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·
Appointment for the next visit,
·
eCRF recording of data collected.
4.1.3
V1 visit
The V1 visit will occur 2 weeks after V0 (± 3 days). The following assessments will be conducted
at V1:
·
Physical examination and vital signsassessment, according to Sections 4.2.1.2 and 4.2.1.5,
·
Weight and calculation of BMI,
·
Blood and urine sample collection for haematology, blood chemistry, urinary analysis
according to Section 4.2.1.8,
·
Query for changes in concomitant medications,
·
Recording of AEs (if any),
·
Appointment for the next visit,
·
eCRF recording of data collected.
4.1.4
V2 visit
The V2 visit will occur 4 weeks after V0 (± 4 days).
The day before V2 the patient will go on site to be administered the IMP at 20:00. The day of V2
the patient must be present on site around 7:30 as a blood sample for PK will be collected in the
morning of V2 before the IMP administration that will take place at 08:00. Patients can, but are
not forced to, spend the night at the site between these 2 drug administrations, upon agreement
between both parties. Patients who leave far away from the investigational site and cannot be
hospitalized during the night before V2 for logistical reasons are allowed to take the evening study
treatment at home on the day before V2. In this case, the time of dosing must be set by the study
team, depending on the time of planed first PK blood sampling at V2, allowing a 12-hour interval
between last drug intake and blood sapmpling. If the patient cannot take the drug at the exact time
requested by the hospital, he must note the actual time of drug intake. Patients who do not spend
the night in the hospital must be provided with a sterile container to collect morning urine. It will
be given to the patient at V1 for those who will not come to the hospital for drug administration
on the day before V2.
The following assessments will be conducted at V2:
·
Physical examination and vital signsassessment, according to Sections 4.2.1.2 and 4.2.1.5,
·
Weight and calculation of BMI,
·
12-lead ECG (Section 4.2.1.6),
·
 Blood and urine sample collection for haematology, blood chemistry, urinary analysis
according to Section 4.2.1.8,
·
Crystalluria analyses according to Section 4.2.1.9,
·
PK blood samples collection according to Section 4.2.2.2,
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·
Query for changes in concomitant medications,
·
Recording of AEs (if any),
·
Pregnancy test in WOCBP. In addition to tests performed at hospital visits, pregnancy tests
will be performed at monthly intervals during treatment and until the end of relevant
systemic exposure. If a positive result is detected with urine pregnancy test, a serum
pregnancy test will be performed to confirm the results.
·
Dispensation of study product to the patient,
·
Appointment for the next visit,
·
Patients will be given a prescription for blood sampling (creatininemia and eGFR) to be
performed at V2 + 1 month in a local laboratory. Results of these analyses will be sent to
the site in real time,
·
eCRF recording of data collected.
4.1.5
V3 visit
The V3 visit will occur 9 weeks after the V2 (± 4 days).
The following assessments will be conducted:
·
Physical examination and vital signsassessment, according to Sections 4.2.1.2 and 4.2.1.5,
·
Weight and calculation of BMI,
·
12-lead ECG (Section 4.2.1.6),
·
Blood and urine sample collection for haematology, blood chemistry, and urinary analysis
according to Section 4.2.1.8,
·
Query for changes in concomitant medications,
·
Recording of AEs (if any),
·
ALSFRS-R measurement,
·
ALS-MITOS measurement,
·
King’s College score measurement,
·
Bioelectrical Impedance Analysis
·
C-SSRS evaluation,
·
SVC assessment,
·
Sniff test7,
·
ABG,
·
Collection of blood samples for biomarkers analysis according to Section 4.2.2.3,
7 The sniff test is optional. It will be performed only in sites that have the equipment and resources to perform this
test.
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·
Pregnancy test in WOCBP. In addition to tests performed at hospital visits, pregnancy tests
will be performed at monthly intervals during treatment and until the end of relevant
systemic exposure. If a positive result is detected with urine pregnancy test, a serum
pregnancy test will be performed to confirm the results.
·
Dispensation of study product to the patient,
·
Appointment for the next visit,
·
 Patients will be given a prescription for blood sampling (creatininemia and eGFR) to be
performed at V3 + 1 month and V3 + 2 months in a local laboratory. Results of these
analyses will be sent to the site in real time,
·
eCRF recording of data collected.
4.1.6
V3bis visit
The V3bis visit will occur 6.5 weeks after the V3 visit (± 4 days).
The following assessments will be conducted:
·
Physical examination: cardiac auscultation, heart rate, systolic and diastolic blood
pressure),
·
12-lead ECG,
·
Blood sample collection for measurement of electrolytes (Na, K, Ca, Cl, Mg, Ph, HCO3),
BNP, troponin, D-Dimers, INR, and prothrombin time.
For patients who have already completed the V3 visit and are very close (≤2 weeks) to the V4 visit
when the decision is made to add the V3bis visit, a phone call should be made to investigate the
patient’s condition. If any sign or symptom is mentioned, the patient should come to the hospital
as soon as possible for further investigations, otherwise the V3bis visit will not be performed and
the patient will undergo the V4 visit as planned.
For patients who have completed the V3 visit and have the V4 visit expected in more than 2 weeks
but less than 6.5 weeks when the decision is made to add the V3bis, the V3bis visit should be made
as early as possible, depending on the site’s and patient’s possibilities. If an onsite visit is
impossible, a phone call must be made to investigate the patient’s condition.
4.1.7
V4 visit
The V4 visit will occur 6.5 weeks after the V3bis (± 4 days).
The following assessments will be conducted:
·
Physical examination and vital signsassessment, according to Sections 4.2.1.2 and 4.2.1.5,
·
Weight and calculation of BMI,
·
12-lead ECG (Section 4.2.1.6),
·
Blood and urine sample collection for haematology, blood chemistry, and urinary analysis
according to Section 4.2.1.8,
·
Query for changes in concomitant medications,
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·
Recording of AEs (if any),
·
ALSFRS-R measurement,
·
ALS-MITOS measurement,
·
King’s College score measurement,
·
Bioelectrical Impedance Analysis,
·
C-SSRS evaluation,
·
Patient’s completion of ALSAQ-40,
·
SVC assessment,
·
Sniff test8,
·
ABG,
·
International Normalized Ratio (INR) if CSF sampling is planned,
·
Collection of blood, urine and CSF samples for biomarkers analysis according to Section
4.2.2.3,
·
 Pregnancy test in WOCBP. In addition to tests performed at hospital visits, pregnancy tests
will be performed at monthly intervals during treatment and until the end of relevant
systemic exposure. If a positive result is detected with urine pregnancy test, a serum
pregnancy test will be performed to confirm the results.
·
Appointment for the next visit,
·
eCRF recording of data collected.
4.1.8
FU visit – V-FU
The V-FU will occur 4 weeks (± 1 week) after V4.
The following assessments will be conducted:
·
Physical examination and vital signsassessment, according to Sections 4.2.1.2 and 4.2.1.5,
·
Weight and calculation of BMI,
·
12-lead ECG (Section 4.2.1.6),
·
Crystalluria analyses according to Section 4.2.1.9,
·
Blood and urine samples collection for haematology, blood chemistry, and urinary analysis
according to Section 4.2.1.8,
·
Serum pregnancy test,
8 The sniff test is optional. It will be performed only in sites that have the equipment and resources to perform this
test.
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·
Query for changes in concomitant medications,
·
Recording of AEs (if any),
·
eCRF recording of data collected.
4.1.9
Premature discontinuation visit
Patients who prematurely withdraw from the study for any reason (Section 5.3), should be
scheduled for a final visit as soon as possible and no later than 4 weeks after the last IMP intake.
The following assessments will be conducted:
·
Physical examination and vital signsassessment, according to Sections 4.2.1.2 and 4.2.1.5,
·
Weight and calculation of BMI,
·
12-lead ECG (Section 4.2.1.6),
·
Blood and urine sample collection for haematology, blood chemistry, and urinary analysis
according to Section 4.2.1.8,
·
Crystalluria analyses according to Section 4.2.1.9,
·
Query for changes in concomitant medications,
·
Recording of AEs (if any),
·
ALSFRS-R measurement,
·
ALS-MITOS measurement,
·
King’s College score measurement,
·
Bioelectrical Impedance Analysis,
·
C-SSRS evaluation,
·
Patient’s completion of ALSAQ-40,
·
SVC assessment,
·
Urine pregnancy test in WOCBP,
·
Sniff test9,
·
ABG,
·
International Normalized Ratio (INR) if CSF sampling is planned,
·
Collection of blood, urine and CSF samples for biomarkers analysis according to Section
4.2.2.3,
·
eCRF recording of data collected.
9 The sniff test is optional. It will be performed only in sites that have the equipment and resources to perform this
test.
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4.2
SPECIFIC ASSESSMENTS
4.2.1
Measurements of the primary variable
Safety assessment
The safety will be assessed on the occurrence of AEs (including SAEs, TEAEs, AESIs (see Section
7).
Identified AEs will be characterised in relation to type, seriousness, incidence, severity, and
relationship to study treatment. Safety will be monitored over the course of the study by a DSMB.
The percentage of patients requiring dosing interruption or definitive treatment discontinuation
due to toxicity will be recorded.
Abnormal laboratory values, vital signs, ECG and other objective measurements
Laboratory values (Section 4.2.1.8), crystalluria (Section 4.2.1.9), physical examination (Section
4.2.1.2), vital signs (Section 4.2.1.5), ECGs (Section 4.2.1.6) and other objective measurements
will be collected in related pages of eCRF. In addition, any of the abovementioned should be
reported as AE if assessed as clinically significant by the investigator and as SAE or AESI if it
meets the corresponding criteria (see Section 7.3).
In the relevant page of the eCRF, a clinical diagnosis should be recorded rather than the abnormal
value itself, if this is available.
Physical examination
A physical examination will be performed at each visit. It will include the examination of general
appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, lymph
nodes, and neurological examination. Height in centimetres (cm) will be measured at screening.
Body weight (to the nearest 0.1 kilogram [kg]) will be measured in patients’ underwear.
If indicated based on medical history and/or symptoms, additional exams will be performed.
Information about all physical examinations must be present in the source documentation at the
study site.
Neuropsychological assessment
In order to assess the presence of active psychiatric illnesses, including dementia, patients will
undergo a neuropsychological evaluation during the screening visit. The investigator will conduct
the visit and perform a basic neuropsychiatric evaluation. No formal tests will be required.
C-SSRS evaluation
Considering the stage of development of IFB-088 (phase 2 with limited safety data in healthy
volunteers), suicidal risk will be evaluated at screening and throughout the study using the
Columbia-Suicide Severity Rating Scale.
Vital signs
This will include temperature, systolic and diastolic arterial pressure and heart rate. Information
about the vital signs must be present in the source documentation at the study site. Blood pressure
and heart rate will be measured after the patient has rested for 5 minutes, in both supine position
and standing.
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Electrocardiogram
A standard 12-lead ECG will be performed in triplicates in a resting position. Prior to the recording
the patient should be at rest for at least 5 minutes. The ECG printout will be reviewed by the
investigator.
Laboratory assessments
Accredited local and central laboratories will be used for analysis of specimens collected at each
visit, according to Table 3. Analyses will include:
·
Complete laboratory evaluations (hematology, biochemistry, electrolytes, liver function,
renal function, urinalysis) for safety assessment,
·
Biomarker assessment (Section 4.2.2.3),
·
Pregnancy test,
·
Crystalluria (Section 4.2.1.9),
·
PK.
Laboratory values that exceed the thresholds of normal laboratory values must be commented by
the investigator on source documents and respective patient’s laboratory eCRF page.
For each visit, the drawn amount of blood, urine and CSF required is detailed in Table 3.
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Safety
Serum (serum-
separating
renal
a
blood RNA
aselin
V-
Premature
heparin tube)
X
X*
X
X
X
X
X
X
Plasma
test
DocuSign Envelope ID: 2F39C862-D120-4D43-A806-B09D08E1B58F
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Table 3 – Schedule and location of the blood, urinary and cerebrospinal fluid tests
Sample
Assessment
Screening
B
(V0) 
e
V1
V2
V3
V3bis
V4
FU
discontinuation
Whole blood
(EDTA/lithium
(haematology)
X
X*
X
X
X
X
X
X
Safety
(electrolytes,
biochemistry,
a
a a
X a a
tube)
liver function,
function)
(EDTA tube)
Biomarkers
X
X
X
X
Whole blood
(PAXgene
Biomarkers
X
X
X
tube)
Plasma
(lithium
PK
X
heparin tube)
Plasma
Efficacy
(lithium
(arterial blood
X
X
X
X
heparin tube)             gases)
Urine
Safety
X
X*†
X
X
X
X
X
X
Urine               Crystalluria                                                           X                                                  X
X
Urine               Biomarkers                                  X                                                               X                               X
Blood/urine
Preg
n
ancy
X**
X***
X***
X***
X***
X**
X***
CSF
Biomarkers
X
X
X
CSF: cerebrospinal fluid, EDTA: ethylenediaminetetraacetic acid, V: visit, FU: follow-up.
* If needed, based on investigator's judgement.
† Additional urine analysis (dipstick) at V0 + one week.
a Additional blood sampling for creatinine measurement at V0 + one week.
a a Additional blood sampling for creatinine measurement and calculation of eGFR at V2 + 1 month.
a a a Additional blood sampling for creatinine measurement and calculation of eGFR at V3 + 1 month and V3 + 2 months.
** Blood pregnancy test at screening and FU visit (V-FU).
*** Urine pregnancy test on a monthly basis until end of exposure to study treatment.
Bio
Quantity
bank      per visit
20 ml
X
20 ml
X
5 ml
10 ml
2 ml
50 ml
50 ml
X          100 ml
2 ml/1
ml
X
1.8 ml
Laboratory
Local
Local
Central
Central
Central
Local
Local
Central
Central
Local
Central
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Blood and urine safety analysis
Blood and urine safety analyses will be performed at each visit after screening, except at baseline
(V0) unless required by occurrence of intercurrent event since screening. Blood will be drawn via
a hypodermic needle inserted into a vein in the arm and collected in the appropriate tube(s),
according to Table 3. The patient must be fasting overnight from 22:00. Urine specimens will be
obtained by providing participants with a collection cup and instructions for the collection.
Further details on blood and urine sample processing, storage and shipping procedures will be
provided in the laboratory procedures manual (LPM) provided by the sponsor.
The following parameters will be assessed for safety assessment:
Haematology
Haematology will include count of red blood cells, haemoglobin, haematocrit, total white blood
cells count, platelet count, and a differential count including neutrophils, lymphocytes, monocytes,
eosinophils, basophils.
Biochemistry
Biochemistry will include glucose, total cholesterol, high-density lipoprotein (HDL) cholesterol
and calculated low-density lipoprotein (LDL) cholesterol, triglycerides, C-reactive protein,
troponin T, creatine kinase, and uric acid.
Electrolytes
Electrolytes will include sodium, potassium, chloride, bicarbonate, calcium, magnesium,
phosphorus.
Renal function
Renal function panel will include creatinine, blood urea nitrogen, estimated glomerular filtration
rate, total protein.
Liver function
Liver function panel will include total protein, albumin, total bilirubin, direct bilirubin, alkaline
phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-
glutamyl transferase (GGT), lactate dehydrogenase (LDH).
According to section 4.4 of riluzole SmPC, ALT should be measured every month during the first
3 months of treatment, every 3 months during the remainder of the first year, and periodically
thereafter. This monitoring should be performed more frequently in patients with ALT increase
under treatment. Depending on the date when riluzole has been initiated and the kinetics of ALT,
additional measurements of ALT might therefore be necessary.
Urinary analysis
It includes blood, leukocytes, pH, glucose, and proteinuria assessed by means of commercial urine
dipsticks. In case of proteinuria ≥ 30 mg/dL on the dipstick, 24-hour protein is also performed.
Urinary analysis will also include measurement of beta 2 microglobuline or albumin-to-creatinine
ratio in mg/g or mg/mmol, microalbumine, creatinine, and proteins, and cytobacteriological
examination of urine (CBEU). All these analyses will be performed in a spot urine sample.
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Crystalluria
Microscopic analysis of urine will be performed to investigate drug-related crystalluria. Sample of
first-morning micturition will be collected at the V2 visit. The sample will be collected by the
hospital staff if the patient has been hospitalised the day before (see Section 4.1.4), or by the
patients themselves if they have spent the night outside the hospital. In this case, patients will
receive a sterile dedicated container either on the day before the V2 visit when they go on site for
the IMP administration for PK assessment, or at the end of the V1 visit for those who will take the
evening treatment at home before V2. A sample of 50 ml will be frozen at -20°C and sent to a
central laboratory that will perform microscopic analysis within 7 days after urine collection. Urine
freezing should be done within 3h of collection.
Crystalluria will also be investigated at the V-FU visit or at the premature discontinuation visit if
any. Urine will be collected when the patient arrives in the hospital for his visit.
Pregnancy testing
All female patients of childbearing potential will have to perform a blood beta-human chorionic
gonadotropin (beta-HCG) testing at screening. For WOCBP, high sensitivity urine pregnancy test
will be performed at baseline and repeated on a monthly basis during treatment and until the end
of relevant systemic exposure, as well as in case of premature discontinuation and at any time if
pregnancy is suspected (sensitivity 25 mIU/ml or more).
In case of pregnancy, collection of information is needed as described in Section 7.8.
4.2.2
Measurements of secondary and exploratory variables
Efficacy assessment
Efficacy assessment will be performed at baseline (V0), 3 months (V3) and 6 months (V4). It will
consist of:
·
ALSFRS-R score,
·
ALS-MITOS score,
·
King’s College score,
·
Assessment of respiratory function: SVC and ABG. Sniff test will be optional, performed
in sites that have the equipment and resources to perform it.
·
Bioelectrical Impedance analysis
The ALSFRS-R, which compared to ALSFRS includes also respiratory function, is the most
widely used and validated rating instrument for monitoring the progression of disability in patients
with ALS. It consists of a disease-specific questionnaire with 12 questions aimed at assessing
functionality [30-32]. Functional decline averages about one point per month in untreated patients
[33].
The ALS-MITOS score is a more recent staging system composed by 4 key domains included in
the ALSFRS-R (walking/self-care, swallowing, communicating and breathing). It is a validated
tool for predicting long-term survival of ALS patients [34, 35].
The King’s College score is based on the number of neurological regions affected and requirement
for gastrostomy or non-invasive ventilation [36, 37]. While ALS-MITOS staging has greater
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resolution for late disease stage corresponding to functional impairment, King’s College score is
able to differentiate early to mid-disease better, making the two systems complementary [38].
The monitoring of respiratory function is achieved by the measurement of SVC, assessed by
spirometry: the patient is asked to take a breath as deep as possible, make a tight seal around the
device mouthpiece, and then exhale. In SVC assessment, exhalation is performed slowly. SVC is
simple, easy to perform and convenient for serial measurements over a long time to evaluate
disease progression [39]. Recently, SVC has been chosen more and more frequently over forced
vital capacity (FVC) test in ALS clinical trials as it is easier to perform for the patient while
providing equivalent information [40]. However, it can be difficult for bulbar-onset ALS patients
who experience facial weakness. The sniff test is a simple, portable, inexpensive test that expects
patients to inhale through their noses with one nostril occluded and a probe connected to a pressure
transducer. This test is easy to perform also for patients with facial weaknesses [39].
ABG test measures the pH and the levels of oxygen and carbon dioxide in the blood from an artery.
ABG is a sensitive and inexpensive tool for monitoring respiratory function in ALS patients, and
turned out to correlate with FVC. ABG does not require patient collaboration and is not influenced
by bulbar involvement [41]. Arterial blood samples will be drawn through radial arterial puncture
into heparin - lithium Vacutainer polyethylene tubes and immediately analysed using blood gas
analyser, routinely calibrated, as appropriate.
Bioelectrical Impedance analysis will be performed using the non-invasive device BIODY
XPERTZM, commercialized by Aminogram. The device is maintained by the patient on his ankle,
in seated position, during approximately one minute, during which various parameters are recorded
and proceeded by a software. All sites will be trained by Aminogram prior to utilization of the
device. Once trained, members of the study team will be allowed to train additional members.
Pharmacokinetic assessment
Blood sampling for PK assessment will be performed at the V2 visit. The day before V2 the patient
will go on site to be administered the IMP at 20:00. If the patient cannot come to the hospital on
the day before V2, he will take study treatment at home at the time requested by the site (see
Section 4.1.4). The day of V2 the patient will be administered again the IMP at 08:00. The blood
samples for PK will be collected in the morning of V2. Patients can, but are not forced to, spend
the night at the site between these 2 drug administrations, upon agreement between both parties.
Venous blood samples (10 mL) for the determination of plasma concentrations of IFB-088 and its
hydroxylated metabolite IFB-139 will be drawn by direct venipuncture or via an intravenous
catheter into heparin - lithium Vacutainer polyethylene tubes (5x2mL). Samples will be collected
at the following time points in the morning: pre-IMP dose, 1, 2, 4 and 6 hours post dose. The actual
date and time of each blood sample collection will be recorded.
IFB-088 and IFB-139 concentrations will be measured within one week, using a validated high-
performance liquid chromatography with tandem mass spectrometry (HPLC/MS-MS) method.
After collection, plasma samples will be stored at -80°C pending analyses. Details of PK blood
sample processing, storage and shipping procedures will be provided in the LPM provided by the
sponsor.
Biomarkers assessment
Potential biomarkers known to be associated with the evolution of the disease and potentially
modulated by IFB-088 treatment will be assessed before and during study treatment. Blood, urine
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and CSF samples will be collected for this assessment (see Table 3). Further details on blood, urine
and CSF sample processing, storage and shipping procedures will be provided in the LPM
provided by the sponsor. Frozen samples will be kept in a biobank for further analyses (see Section
4.2.2.5).
Blood biomarkers
Blood will be collected in 2 different types of tubes to measure potential biomarkers in both plasma
and whole blood (messenger RNA [mRNA], microRNA [miRNA]). Blood should be first drawn
in Ethylenediaminetetraacetic acid (EDTA) tubes and then in PAXgene Blood RNA Tube, as
described below.
Plasma
Blood for plasma biomarkers assessment will be collected at V0, V3 and V4 according to schedule
of activities (Sections 3.7 and 4.1) in 2 tubes of 10 ml containing EDTA properly labelled with
patient identification. After processing, plasma will be aliquoted in and stored at -80°C pending
analyses. Samples will be stored at a facility designated by the sponsor. The following parameters
will be analysed at a laboratory approved by the sponsor:
·
NfL light chain: at baseline and 6 months,
·
NfL heavy chain: at baseline and 6 months,
·
TDP-43: at baseline and 6 months,
·
Inflammation biomarkers (interleukin [IL]-6, tumour necrosis factor-α [TNFα], interferon
γ [IFNγ], IL-1β, IL-8, IL-10, monocyte chemoattractant protein-1 [MCP-1], nerve growth
factor [NGF], brain-derived neurotrophic factor [BDNF], vascular endothelial growth
factor [VEGF]), transforming growth factor beta [TGFᵯ]: at baseline, 3 and 6 months,
·
Oxidative stress biomarkers (reactive oxygen species): at baseline, 3 and 6 months.
Unused plasma aliquots will be kept in the biobank (Section 4.2.2.5) for potential further analyses.
Whole blood
For whole blood biomarkers assessment, blood will be drawn at V0 and V4 in PAXgene Blood
RNA tubes. Tubes must be at room temperature prior to use and properly labelled with patient
identification. The tube should be gently inverted 8 to 10 times and store at -80°C pending
analyses. Samples will be stored at a facility designated by the sponsor and will be kept in a
biobank (Section 4.2.2.5) for potential further analyses.
Urine biomarkers
Urine will be collected at V0 and V4.
Urine samples of 100 ml will be collected and stored in accordance with the Urine & Kidney
Proteome Projects standards [42]. Sampling for urine biomarkers and routine safety/crystalluria
must be collected at different time points. After processing the urine will be aliquoted, properly
labelled with patient identification and stored at -80°C pending analyses. Urine samples will be
stored at a facility designated by the sponsor and will be kept in a biobank (Section 4.2.2.5) for
potential further analyses.
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Cerebrospinal fluid biomarkers
CSF will be collected at V0 and V4 in patients willing to undergo lumbar puncture unless they
present any contraindication to CSF sampling. These contraindications include the presence of risk
for increased or uncontrolled bleeding and/or risk of bleeding that if not managed optimally could
place a participant at an increased risk for intraoperative or postoperative bleeding. These could
include, but are not limited to, anatomical factors at or near the LP site (e.g., vascular
abnormalities, neoplasms, or other abnormalities) and underlying disorders of the coagulation
cascade, platelet function, or platelet count (e.g., hemophilia, Von Willebrand’s disease, liver
disease). They also include anticipated need, in the opinion of the Investigator, for administration
of any antiplatelet or anticoagulant medication (e.g., clopidogrel) that cannot be safely continued
or held for an LP procedure, if necessary, according to local or institutional guidelines and/or
Investigator determination.
INR should be measured prior to CSF sampling.
Patients with contraindications to lumbar puncture can be included in the study but will not
undergo CSF sampling.
Lumbar puncture will be performed by a clinician according to the site's usual practice. The CSF
will be collected and then aliquoted and properly labelled with patient identification. The tubes
will be snap frozen in liquid nitrogen and immediately stored at -80°C, pending analyses. CSF
samples will be stored at a facility designated by the sponsor and will be kept in a biobank (Section
4.2.2.5) for potential further analyses.
Quality of life assessment
QoL will be assessed using the validated ALSAQ-40 questionnaire, specifically used to measure
the subjective well-being of patients with ALS [43]. ALSAQ-40 has psychometric robustness, and
it provides an interpretable picture of the impact of the condition on the subjective functioning and
well-being of patients on areas that are of concern to them. It provides scores for 5 areas of health
state: physical mobility (10 items), activities of daily living and independence (10 items), eating
and drinking (3 items), communication (10 items), and emotional reactions (10 items). The
questionnaire must be completed by the patient. Patients need to tick the box which best describes
his/her own experience or feelings. Patients should try to answer every question even though some
may seem rather similar to others, or may not seem relevant to them. QoL will be assessed as the
change in absolute value and percentage of ALSAQ- 40 between baseline and 6 months.
Biobank
Blood, urine and CSF samples will be stored at -80°C at a facility designated by the sponsor to
measure biomarker candidates as needed. These samples will be kept for 5 years after final
database lock for further analysis and then destroyed if unused.
5.
STUDY POPULATION
The study population will consist of patients with bulbar-onset ALS. A total of 50 patients from
France and Italy will be enrolled in the study, primarily through University hospitals setting. A
voluntary signed ICF will be obtained from the patients prior to participation in the study.
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The recruitment of patients is competitive and will be terminated once the required sample size
has been reached.
Patients who meet all the following inclusion criteria and none of the exclusion criteria will be
eligible to participate in the study.
5.1
INCLUSION CRITERIA
Patients must satisfy all the following inclusion criteria to be enrolled in the study:
1.
 Diagnosis of probable or definite ALS according to the revised El Escorial criteria [29],
with bulbar onset of disease, familial or sporadic form,
2.
Onset of symptoms ≤ 18 months prior to screening, as reported by the patient,
3.
Adult males or females, aged at least 18 years old,
4.
SVC > 60% of predicted value for age and sex,
5.
ALSFRS-R score ≥ 36,
6.
Treatment with riluzole 100 mg/day, at stable dose since at least one month and well
tolerated,
7.
 Male or female patient of childbearing potential10 who agrees to use highly effective
mechanical contraception methods (sexual abstinence, intrauterine device, bilateral tubal
occlusion, vasectomised partner) throughout the study, and for 3 months after the end of the
treatment,
8.
Patient who read, understood and signed the ICF,
9.
Patient who is willing to adhere to the study visit schedule and is capable to understand and
comply with protocol requirements.
5.2
EXCLUSION CRITERIA
A patient will not be eligible for inclusion in this study if at least one of the following criteria
applies:
1.
Known other significant neurological disease(s),
2.
Serious illness(es) or medical condition(s) (e.g. unstable cardiac disease, cancer,
hematologic disease, hepatitis or liver failure, renal failure) that is not stabilised or that
could require hospitalisation and may jeopardise the participation in the study,
3.
Abnormal renal function at screening defined as estimated glomerular filtration rate (eGFR)
< 60 mL/min/1.73m2,
10 According to the CTFG guideline V2.1 September 2020, a woman is considered of childbearing potential (WOCBP), i.e., fertile,
following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include
hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months
without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used
to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the
absence of 12 months of amenorrhea, a single FSH measurement is insufficient. A man is considered fertile after puberty unless
permanently sterile by bilateral orchidectomy.
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4.
Abnormal liver function at screening defined as total bilirubin levels >1.5 ULN, and/or AST
and/or ALT >3 ULN,
5.
Neutropenia (ANC <1.5 x 109/L) at screening,
6.
Other causes of neuromuscular weakness,
7.
Non progressive or very rapidly progressing ALS (ALSFRS-R decline from disease onset
to randomisation ≤ 0.1 / month or ≥ 1.2 / month)11,
8.
Non-invasive ventilation,
9.
Tracheotomy,
10. Dementia or other severe active psychiatric illness, including suicidal ideation assessed
using the Columbia-Suicide Severity Rating Scale (C-SSRS),
11. Patient with a significant pulmonary disorder not attributed to ALS or who require
treatments that might complicate the evaluation of the effect of ALS on respiratory function,
12. Patient treated by edaravone for ALS,
13. Patient using unauthorised concomitant treatments, namely moderate or strong inhibitors or
inducers of CYP1A2, strong inhibitors or inducers of CYP2D6 or 2C19 and strong
inhibitors of OCT2, as listed in Section 6.2. Combined oral contraceptives containing
ethinylestradiol are forbidden concomitant medications,
14. Smoker of > 10 cigarettes per day (e-cigarettes and nicotine patches are permitted),
15. Known hypersensitivity to any of the ingredients or excipients of the IMPs,
16. Pregnant, lactating women,
17. Patient who participated in another trial of investigational drug(s) within 30 days prior to
randomisation, or 5 half-lives of the previous investigational product, whichever is longer,
18. Patient who has forfeited their freedom by administrative or legal award, or who is under
guardianship or under limited judicial protection.
5.3
WITHDRAWAL OF THE PATIENT
Patients may withdraw from the study at any time without having to provide justification and
without penalty to their continuing medical care.
The investigators may withdraw patients from the study for the following reasons:
·
Patient withdrawing the consent,
·
 If, in the investigator's opinion, continuation in the study would be detrimental to the
patient’s well-being, in particular in case of an AE,
·
 If, in the investigator’s opinion, the patient is unable to maintain the schedule or is non-
compliant,
11 Decline will be calculated as follows: 48 minus ALSFRS-R score at the time of inclusion divided by number of
months since occurrence of first symptoms of disease, as reported by the patient.
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·
If the patient becomes pregnant during the study,
·
If the patient meets one of the following criteria for permanent drug discontinuation:
o Increased ALT or AST levels ≥ 5 x ULN.
o ALT or AST > 3 ULN and total bilirubin levels > 2 ULN.
o Neutropenia.
o Symptoms evocative of interstitial lung disease: dry cough and/or dyspnoea,
bilateral diffuse lung opacities.
·
 Lost to FU. A participant will be considered lost to FU if he/she repeatedly fails to return
for scheduled visits and is unable to be contacted by the study site. Site personnel are
expected to make diligent attempts to contact participants who fail to return for a scheduled
visit or are otherwise unable to be followed up by the site.
The date of withdrawal and the principal reason for withdrawal must be recorded in the eCRF and
in the patient’s records. No additional data will be collected for withdrawn patients. Every effort
must be made to contact patients who did not come back for a planned visit/contact.
Every effort will be made to ensure that patients who do not complete all study visits return to the
site for the premature discontinuation visit (Section 4.1.9), as soon as possible and no later than 4
weeks after the last IMP intake. Patients who withdraw due to an AE or SAE will be given
appropriate care under medical supervision until the symptoms resolve or the patient’s condition
becomes stable.
Patients who prematurely withdrew from the study or are lost to FU will not be replaced by new
patients.
Any temporary discontinuation of 10 days or less, related to any medical condition that prevents
treatment administration based on investigator’s judgment, should be allowed and recorded in the
eCRF. Any associated AE shall be reported. In case of treatment discontinuation above 10 days,
the patient should be withdrawn from the study.
If the participant withdraws consent for disclosure of future information, the sponsor may retain
and continue to use any data collected before such a withdrawal of consent. If a participant
withdraws from the study, they may request destruction of any samples taken and not tested, and
the investigator must document this in the site study records.
6.
STUDY PRODUCTS
The study product is defined as “a pharmaceutical form of an active substance or placebo being
tested or used as a reference in a clinical study, including products already with a marketing
authorisation but used or assembled (formulated or packaged) in a way different from the
authorised form, or when used for an unauthorised indication, or when used to gain further
information about the authorised form”. In this trial, the study products are IFB-088 and its
matching placebo.
IFB-088 and placebo will be provided as white, oblong, immediate release 200 mg tablets, with
the same composition except for the active ingredient, i.e. 25mg of IFB-088 per tablet for the IFB-
088 tablets.
IFB-088 and placebo tablets excipients are listed in Table 4.
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Table 4 - Composition of IFB-088 and placebo tablets
Compound
IFB-088 acetate salt
Microcrystalline cellulose
Silica, colloidal hydrated
Crospovidone
Magnesium stearate
Function
Active pharmaceutical ingredient
Filler
Glidant
Disintegrant
Lubricant
6.1
INVESTIGATIONAL MEDICINAL PRODUCTS
6.1.1
Dosage and dosage schedule of the investigational medicinal products
The test product, IFB-088, will be administered in 50 mg/day dosage consisting of two uptakes of
25 mg each, as an add-on therapy to riluzole 100 mg. The placebo will be administered in two
uptakes, as an add-on therapy to riluzole 100 mg.
Administration of riluzole 100 mg, tablet or suspension, will be at the patient's and/or investigator's
choice, as per summary of product characteristics [44]. The daily dose of 100 mg will be taken in
two 50 mg doses every 12 hours, at the same time than the IMPs.
6.1.2
Administration of the investigational medicinal products
Only patients enrolled in the study will receive the study products and only trained and authorised
site staff will handle and supply them. Patients will receive the IMPs kit directly from the
investigator or the medicine will be sent directly to the patient from the site pharmacy.
The patients will receive the IMP at baseline visit (V0: 2 bottles), V2 (2 bottles) and V3 (2 bottles)
visits. They will be instructed to take the IMP orally twice a day (morning and evening uptakes).
Intervals for dosing should ideally be about 12 hours (± 1 hour). Tablets shall be swallowed with
a glass of water 30 minutes before the meal, in fasting condition. For patients who have swallowing
difficulties, tablets can be taken in a spoon filled with jellified water. IFB-088 and riluzole will be
taken at the same time. Dosage modifications are not permitted. However, in case of unplanned
dosage modification by the patient, it shall be documented in the eCRF. Missed doses will not be
made up for. In case of vomiting shortly after ingestion of the study product, the patient will leave
out the potential missed dose and will take the next dose as normal. Study product doses withheld
due to toxicities and AEs will not be made up later. Should the patient or the investigator wish to
discontinue treatment for any reason, they may do so at any time. The date of the last uptake will
be documented in the eCRF.
6.1.3
Supply and storage conditions of the investigational medicinal products
IFB-088 and placebo supplied by the sponsor to be used in this study will be manufactured, tested,
handled and stored according to current Good Manufacturing Practice (GMP) requirements for
clinical trials.
The sponsor will provide the study centre with the test product and the placebo. The investigator
or pharmacist (if applicable) will receive numbered products. The investigator/pharmacist is
responsible for a safe and proper handling and storage of the study drug at the investigational site.
The study drug must be stored in a locked facility with restricted access to the
investigator/pharmacist and authorised personnel. The study products have to be stored at room
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temperature. The investigator or designee must confirm appropriate temperature conditions have
been maintained during transit for each study product received.
The investigator and/or a pharmacist or another appropriately trained individual is obliged to
document the receipt, dispensation, and return of all study products received during this study.
Records on receipt, use, return, loss, or other disposition of study drugs must be maintained. The
investigator and/or a pharmacist or another appropriately trained individual must sign the receipt
forms. Records on study drug delivery to the site, the inventory at the site, the use by each patient,
and the return to the sponsor must be maintained by the investigator and/or a pharmacist or another
appropriately trained individual at the investigational site. Patients will be asked to return all
unused study drug and packaging at each visit, and at the time of study drug discontinuation. The
following information will be recorded in the patient's file: dates, quantities, batch numbers, and
the unique code numbers assigned to the study products and the patients. The investigators must
maintain records documenting that the patients were provided with their respective doses specified
in the protocol. Furthermore, they should reconcile all study drugs received from the sponsor. It is
the responsibility of the investigator to give reasons for any discrepancies in IMPs accountability
All remaining IMPs, used and unused, shall be collected and returned to the sponsor for destruction
at the end of the study.
6.1.4
Packaging and labelling of the investigational medicinal products
The study products will be packaged and labelled according to current GMP guidelines, good
clinical practice (GCP) guidelines, and national legal requirements and instruction will be given
in local language. KLS will be responsible for label compliance. Eurofins Gent will be responsible
for the packaging, and Eurofins St Gely will be responsible for the labelling and shipping of the
IMP and placebo to the investigating sites.
IFB-088 and placebo tablets are packaged in 40 mL high-density polyethylene bottles with
polypropylene screw cap lids that contain desiccant. Each bottle contains 65 tablets covering the
needs for a bi-daily administration over one month.
6.2
CONTRAINDICATIONS
Definitive pre- and post-natal developmental toxicity studies with IFB-088 have not been
conducted. For this reason, the use of IFB-088 is contraindicated in women who are pregnant or
lactating.
Edaravone, that is not commercially available in Europe but can be administered via
compassionate use programs, is contraindicated during the whole study period, until completion
of the follow-up visit.
IFB-088 is a substrate of CYP1A2. The concomitant use of drugs that are strong or moderate
inhibitors or inducers of CYP1A2 is not permitted for inclusion in the study or during treatment
(Table 5). The concomitant use of weak inhibitors or inducers of CYP1A2 will be allowed. IFB-
088 is also metabolized, to a lesser extent, by CYP2D6 and CYP2C19. Therefore, concomitant use
of strong inhibitors or inducers of these 2 isoenzymes will be prohibited for inclusion and during
treatment. Finally, IFB-088 is certainly a substrate of OCT2, a renal transporter expressed at the
basal membrane of tubular epithelial cells that might thus be involved in the renal tubular secretion
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of IFB-088. For this reason, strong inhibitors of OCT2 will be prohibited for inclusion and during
treatment. The list of prohibited drugs is displayed in Table 5.
If treatment by one of the abovementioned drugs is required during the study because there is no
therapeutic alternative, treatment with IFB-088 will be interrupted during the administration of the
prohibited therapy and during a period of 5 elimination half-lives of the administered treatment. If
IFB-088 discontinuation lasts more than 10 days, the patient will be withdrawn from the study.
Tobacco consumption exceeding 10 cigarettes per day is prohibited during the study. E-cigarettes
and nicotine patches are allowed.
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Table 5 - Forbidden concomitant medications
CYP1A2
Strong inhibitors
Ciprofloxacin
Enoxacin
Fluvoxamine
Norfloxacin
Moderate inhibitors
Amiodarone
Atazanavir
Cannabidiol
Ethinylestradiol
Fluoxetine
Methoxsalem
Mexiletine
Moclobemide
Oral contraceptives
Paroxetine
Propafenone
Quetiapine
Sertraline
Tipranavir,
Verapamil
Strong inducers
Moderate inducers
Carbamazepine
Lansoprazole
Modafinil
Omeprazole
Phenytoin
Rifampicin
Ritonavir
Teriflunomide
CYP: Cytochrome P450 family.
CYP2D6
Bupropion,
Fluoxetine,
Paroxetine,
Quinidine,
Terbinafine
CYP2C19
Fluconazole,
Fluoxetine,
Fluvoxamine,
Ticlopidine
Rifampicin
OCT2
Cimetidine
Doxepin
Pantoprazole
As in vitro data suggest that CYP1A2 is also the main isoenzyme involved in the metabolism of
riluzole, and according to section 4.5 of riluzole SmPC, it should be noted that inhibitors of
CYP1A2 (e.g. caffeine, diclofenac, diazepam, nicergoline, clomipramine, imipramine,
fluvoxamine, phenacetin, theophylline, amitriptyline and quinolones) could potentially decrease
the rate of riluzole elimination, while inducers of CYP1A2 (e.g. cigarette smoke, charcoal-broiled
food, rifampicin and omeprazole) could increase the rate of riluzole elimination.
6.3
USE OF CONCOMITANT MEDICATIONS
Any medication, investigational agent, or vaccine, including over the counter or prescription
medicines, vitamins, and/or herbal supplements, or other specific categories of interest that the
participant is receiving at the time of enrolment or receives during the study must be recorded
along with:
·
Reason of use,
·
Dates of administration including start and end dates,
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·
Dosage information including dose and frequency for concomitant therapy of special
interest.
Other concomitant medication may be considered on a case-by-case basis by the investigator in
consultation with the sponsor if required. The sponsor should be contacted if there are any
questions regarding concomitant or prior therapy. Patients must be informed by the investigators
about the fact that they may not take any drug, food supplement, vitamins, etc. on their own without
the agreement of their referent investigator.
6.4
COMPLIANCE
Patient compliance with study medication will be assessed at each visit and at the time of study
products discontinuation by the investigator by direct questioning and by recollection of IMP
packaging. Patients will be asked to return all unused study products.
If the time for one visit exceeds the time window, this will be recorded as a deviation from the
protocol. Any deviation from the prescribed dosage regimen is to be recorded in the eCRF.
7.
ADVERSE EVENTS
7.1
DEFINITION OF AN ADVERSE EVENT
According to international conference on harmonisation (ICH), an AE is any untoward medical
occurrence in a patient or clinical investigation subject administered a pharmaceutical product and
which does not necessarily have a causal relationship with this treatment. An AE can therefore be
any unfavourable and unintended sign (including an abnormal laboratory finding), symptom or
disease temporally associated with the use of a medicinal (investigational) product, whether or not
related to the medicinal (investigational) product. A clinically relevant worsening of a pre-existing
condition during the study must also be recorded as an AE.
7.2
DEFINITION OF A TREATMENT EMERGENT ADVERSE EVENT
A TEAE is defined as any AE not present prior to the initiation of the treatments (that is before
baseline visit: V0) or any event already present that worsens in either intensity or frequency
following exposure to the treatments. AEs occurring after subject enrolment (ICF signature) but
prior to first study drug administration will be recorded as a non-treatment emergent adverse event
(NTEAE).
7.3        DEFINITION OF A SERIOUS ADVERSE EVENT
A SAE is defined as any untoward medical occurrence that:
·
Results in death,
·
 Is life-threatening (the term ‘life-threatening’ refers to an event in which the patient was at
risk of death at the time of the event; it does not refer to an event that hypothetically might
have caused death if it was more severe),
·
Requires in-patient hospitalisation or prolongation of existing hospitalisation,
·
Results in persistent or significant disability or incapacity,
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·
Is a congenital anomaly or birth defect.
Medical and scientific judgement should be exercised in deciding whether expedited reporting is
appropriate in other situations, such as important medical events that might not be immediately
life threatening or result in death or hospitalisation but might jeopardise the patient or might require
intervention to prevent one of the other outcomes listed above.
7.4
DEFINITION OF AN ADVERSE EVENT OF SPECIAL INTEREST
An AESI (serious or non-serious) is an AE of scientific and medical concern specific to the
sponsor's product or program, for which ongoing monitoring and rapid communication by the
investigator to the sponsor can be appropriate.
The following will be considered as AESIs:
·
Renal toxicities,
·
 Symptomatic hypotension grade 2 (requiring non-urgent medical intervention) or above
according to common terminology criteria for adverse events (CTCAE) version 5.0,
·
Hypertriglyceridaemia (HTG). A cut-off value is set at triglycerides > 5.7 mmol/L (5.0
g/L) with at least 20% increase compared to baseline value.
7.5
DEFINITION OF A NEW FACT
New information which might alter the current benefit-risk assessment of the IMP or the trial;
modify the use of the IMP, the conduct of the study, or documents related to the trial; or suspend,
modify or terminate the clinical trial.
7.6
DEFINITION OF SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTION
SUSAR is the term used to refer to an adverse event that occurs in a clinical trial subject, which is
assessed by the sponsor and or study investigator as being unexpected, serious and as having a
reasonable possibility of a causal relationship with the study drug.
7.7
RECORDING OF AN ADVERSE EVENT
The investigator must record all AEs presented or reported by the patient in the AE section of the
eCRF. The start date, the actions taken (corrective treatments, dose decrease, temporary or
definitive discontinuation of study product, premature withdrawal from the study, none, other) and
the outcome (ongoing, recovered with/without sequelae, death) must all be recorded, and the
investigator must assess the event in terms of seriousness, severity and relationship to the study
products.
When possible, signs and symptoms should be reported as a diagnosis i.e. the investigator should
avoid reporting only the signs and symptoms. If there is no medical diagnosis and the signs and
symptoms have to be reported, the investigator should record a separate AE for each sign and
symptom.
The severity of the AEs will be judged by the investigator(s) and recorded as follows:
·
Mild: discomfort noticed but no disruption of normal daily activity,
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·
Moderate: discomfort sufficient to reduce or affect daily activity,
·
Severe: inability to work or perform normal daily activity.
The relationship of the AE to the study product will be judged by the investigator(s) and recorded
as follows:
·
Not related: a reaction for which sufficient information exists to indicate that the aetiology
is unrelated to the study drug; the subject did not receive the study medication or the
temporal sequence of the AE onset relative to administration of the study medication is not
reasonable or the event is c1early related to other factors (subject' s clinical state,
therapeutic intervention or concomitant therapy),
·
Unlikely: Does not follow a reasonable temporal sequence from administration of the IMP,
or is most likely related to another aetiology than the trial drug such as the patient’s clinical
state, environmental factors or other therapies,
·
Possibly: a clinical event, including laboratory test abnormality, with a reasonable time
sequence to administration of the drug but which could also be explained by concurrent
disease or other drugs or chemicals,
·
Probably: a clinical event including laboratory test abnormality, with a reasonable time
sequence to administration of the drug, unlikely to be attributed to concurrent disease or
other drugs and which follows a clinically reasonable response on withdrawal (de-
challenge),
·
Definitely: a reaction that follows a reasonable temporal sequence from administration of
the drug, or in which the drug level has been established in body fluids or tissues, that
follows a known or expected response pattern to the suspected drug, and that is confirmed
by improvement on stopping or reducing the dosage of the drug, and reappearance of the
reaction on repeated exposure (re-challenge if applicable).
For safety reporting purpose by the sponsor:
·
Reasonable possibility: possibly, probably, definitely related AEs,
·
No reasonable possibility: not related, unlikely related AEs.
All AEs and SAEs will be collected from the time of signing of the ICF until participation in study
has ended. There is no time limit for investigators for reporting to the sponsor related SAEs they
are made aware of.
Adverse events that begin before the start of study intervention but after signing of the ICF will be
recorded on the AE eCRF (NTEAEs).
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7.8
REPORTING OF SERIOUS ADVERSE EVENTS AND NEW FACTS
The investigator will immediately, i.e. within 24 hours from first knowledge, report, by fax or e-
mail, any SAE occurring during the study to the safety officer (SO) acting on behalf of the sponsor
of the study:
STRAGEN SERVICES S.A.S, 19 rue Jacqueline Auriol, 69008 Lyon, France
Fax number +33 478425571
Email: InFlectisPV@stragen.fr
SAEs must be reported using the supplied SAE/AESI/pregnancy form. The investigator will
complete in English and sign an SAE report form and transmit it to the SO by email or telefax not
later than 24 hours after the first knowledge of the SAE. The SO acknowledges the receipt of the
SAE information by email to the investigational site within one working day. In the absence of
email acknowledging the receipt or in case of issue in sending the fax or email, the investigator
shall contact the SO by any means for ensuring the receipt of SAE information at the earliest
opportunity.
Although all AEs after signing the ICF are recorded in the eCRF, SAEs reporting to sponsor begins
after the participant has signed the ICF and has received study intervention. However, if an SAE
occurs after signing the ICF, but prior to receiving study intervention, it needs to be reported within
the SAE reporting timeframe if it is considered reasonably possibly related to study procedures.
Details of all pregnancies in female participants will be collected for 90 days after end of treatment
(V4). If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of
learning of the pregnancy, using the SAE/AESI/pregnancy form. The sponsor (via Stragen
Services) will then follow up on such pregnancy with the investigator, using a dedicated pregnancy
form, at least until pregnancy outcome. Abnormal pregnancy outcomes, for example, spontaneous
abortion, foetal death, stillbirth, congenital anomalies, and ectopic pregnancy, are considered
SAEs.
New facts which may impact the risk-benefit for enrolled patients and/or impact on the study
conduct may not necessarily fulfil the definition and/or criteria for constituting an SAE. However,
such information shall be provided to the sponsor in accordance with the process described for
SAEs, i.e. within 24h from knowledge and using the SAE/AESI/pregnancy form.
Any FU information will be reported to the SO and to the sponsor as soon as it becomes known,
with the same process and timelines as described here above for initial reports. The sponsor will
ensure that all relevant information about SAE and SUSAR is recorded and reported to the national
competent authorities (CAs) in all member states concerned and to IECs within the applicable
regulation and local specificities.
SAEs occurring after the last study visit will only be reported if the investigator believes that the
event may have been caused by the IMP or a protocol procedure.
Hospitalisation for a diagnosis or therapeutic procedure planned before study enrolment but
performed after the enrolment should not be considered for SAE and should be reported in eCRF
in concomitant procedures page.
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7.9
REPORTING OF ADVERSE EVENTS OF SPECIAL INTEREST
AESIs should be reported via the same process established for SAEs, regardless of seriousness.
AESIs, both serious and non-serious, must be reported within 24h from knowledge using the
SAE/AESI form. The form will be named SAE/AESI/pregnancy form, as it is also used for the
initial notification of pregnancy.
7.10
CLINICAL EVENTS RELATED TO ALS
Clinical events related to ALS or consisting in known ALS complications will be recorded in the
AE section of the eCRF. When serious, these clinical events are exempt from SAE reporting,
unless the investigator deems the event to be related to the administration of the study drug, or
unless the event results in patient’s death: in these 2 cases, the event should be reported as SAE.
The following events will be considered clinical events related to ALS or ALS complications:
· Onset, changes or aggravation of speech and/or voice disorders,
· Onset,
changes
or
aggravation
of
swallowing
disorders
including
drooling,
aspiration/choking,
· Onset, changes or aggravation of emotional disorders, including exaggerated and/or
involuntary emotional responses, alteration and/or lack of control in emotive expression,
fronto-temporal executive dysfunction,
· Onset, changes or aggravation of breathing difficulties,
· Onset, changes or aggravation of muscle and/or joint disorders and their consequences,
including muscle weakness, muscle atrophy/wasting, muscle spasticity, muscle cramps,
fasciculations, stiffness, joint pain and/or contractures, reduced dexterity, wrist drop,
tripping, stumbling, awkwardness, foot drop, spasms, uncontrolled movements,
· Onset, changes or aggravation of upper and/or lower motor neuron signs and symptoms,
including reflexes disorders (abnormal reflexes, hypo/hyperreflexia), abnormal motor nerve
conduction studies.
7.11
TREATMENT OF OVERDOSE
In the event of an overt overdose, with or without adverse event, the investigator should:
·
Contact
the
sponsor
immediately
via
Stragen
Services
using
the
SAE/AESI/pregnancy/overdose form,
·
 Closely monitor the participant for any AE/SAE and laboratory abnormalities as
appropriate and provide supportive care as necessary,
·
Document the quantity of the excess dose in the eCRF.
Decisions regarding treatment interruptions or modifications will be made by the investigator, in
consultation with the sponsor, based on the clinical evaluation of the patient.
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8.
STATISTICS
8.1
STATISTICAL AND ANALYTICAL METHODS
8.1.1
General statistical considerations
Statistical analyses will be performed by the sponsor or under the supervision of the sponsor and
further detailed in the SAP, which will be finalised prior to the unblinding of data and database
lock.
In general, summary tabulations will be presented by treatment arm and will display the number
of observations, mean, standard deviation (SD), median, Q1, Q3 quartiles, minimum, and
maximum for continuous variables, and the number and percent per category for categorical data.
Patient disposition
An accounting of study patients by disposition will be tabulated and the number of patients in each
analysis set will be summarised. Patients who discontinue study treatment and patients who
withdraw from the study, with associated reason(s), will be summarised. A summary of protocol
deviations by treatment arm and the corresponding listing by patient will be generated.
Nominal alpha level of significance
Unless otherwise noted, as the trial is a safety trial and an estimation efficacy study and not
powered for efficacy endpoints, all tests performed on efficacy assessments will be conducted at a
1-sided nominal alpha level of 0.10 and confidence intervals (CIs) will be calculated at 80%, 2-
sided 95% confidence intervals will also be provided.
Missing data handling
As a general rule, missing data will not be replaced. Sensitivity analyses based on multiple
imputation will be proposed and further detailed in the SAP.
Multiplicity
As it is mainly an estimation trial, there is no adjustment for multiplicity.
8.1.2
Sample size
The minimum required sample size for this study has been estimated at 42 evaluable patients.
Since it is an exploratory safety study, it has not been based on a formal sample size calculation.
However, with regard to the primary safety endpoint, it is worth noting that 28 patients enrolled in
the IFB-088 arm will be sufficient to observe at least one SAE which incidence is greater than or
equal to 5% (10% resp.) with a probability of at least 76.2% (94.8% respectively). In addition, 42
patients are also considered sufficient to observe some numerical efficacy signal on some key
parameters. Assuming a 15% drop-out rate, 50 patients will be randomised.
8.1.3
Analysis Sets
The following analysis sets will be considered. Additional details of analysis sets of patients may
be defined in the SAP.
·
Safety set (SS): randomised patients having received at least one dose of the IMPs and
analysed according to the treatment actually received,
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·
Efficacy sets:
o Randomised set (RS): all patients “as randomised” (i.e. according to the treatment
group to which they were randomised, regardless of the treatment actually taken),
o Full analysis set (FAS): as randomised patients having received at least one dose of
the IMPs and having a non-missing baseline value,
o Per protocol set (PPS):
FAS patients fulfilling the following criteria. Criteria definition will be further
detailed during a blinded data review meeting and specified in the SAP:
-
Major inclusion/exclusion criteria satisfied,
-
Absence of relevant protocol violations likely to affect treatment efficacy,
-
Adequate study medication compliance, defined as intake of at least 80% of the
planned total dose.
8.1.4
Population and baseline characteristics description
Demographics, concomitant medications, and other baseline characteristics will be described by
treatment arm according to general considerations. Details will be provided in the SAP.
8.1.5
Efficacy / safety analysis
Primary outcome
Usual descriptive statistics will be used and detailed in the SAP to analyse the safety parameters.
AEs will be classified by system organ class and preferred term using the Medical Dictionary for
Regulatory Activities (MedDRA). AEs will be listed and summarised by, MedDRA preferred
term, severity, and relationship to study drug. In the event of multiple occurrences of the same AE
with the same preferred term in one patient, the AE will be counted once as the occurrence.
Secondary outcomes
Efficacy endpoints
Analyses will be further detailed in the SAP.
The analysis of efficacy endpoints will be primarily performed in the FAS. A secondary analysis
will be proposed in the PPS.
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Change in ALSFRS-R score: from baseline to 6 months will be analysed using a
mixed model for repeated measures (MMRM) assuming missing at random (MAR)
and unstructured covariance matrix and including fixed factors for treatment, visit
(categorical variable), treatment-by-visit interaction, random patient factor and
baseline ALSFRS-R as a continuous covariate. The degrees of freedom will be
estimated using the Kenward-Roger’s approximation. Least square means (LSMs)
of change from baseline and LSM differences in change from baseline between
active doses and placebo will be presented along with 80% and 95% CIs and the
comparison p-value. A one-sided nominal significance level of 0.10 will be used
for treatment comparison. Model assumptions will be checked (plot of studentized
residuals vs predicted values, etc.). If the model assumptions do not hold, a rank
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semi-parametric analysis of covariance (ANCOVA) model (or a rank non-
parametric Quade’s ANCOVA model if the assumptions of this latter do still not
hold) will be proposed instead. As the MAR assumption is untestable and may not
hold for subjects withdrawing at their own will, a sensitivity analysis will be based
on a pattern mixture model that uses a multiple imputation technique analysed with
an ANCOVA with pre specified fixed factors and covariates. The imputation model
will be further clarified in the SAP. Another sensitivity Bayesian analysis using the
historical placebo data from the ProMISe study [26] will be also performed and
further detailed in the SAP. An intrapatient analysis of ALSFRS changes will be
performed.
·
Worsening (i.e. progression to a higher stage at 6 months compared to the baseline
stage defined by ALS-MITOS score): the proportion of progressors will be
compared between both treatment groups. The difference in binomial proportions
will be estimated along with an exact 95% CI. A sensitivity Bayesian analysis using
the historical placebo data from the ProMISe study [26] will be also performed and
further detailed in the SAP. Progressors will also be analysed in a logistic regression
model adjusting for treatment and additional relevant covariates (specified in the
SAP). The treatment effect will be estimated in terms of an odds ratio associated
with the 95% CI and p-value and also in terms of a difference in progression rates
with its 95% CI using the method proposed by Ge and al. [45].
·
Change in King’s Çollege score: the endpoint will be analysed with an approach
similar to the analysis of ALS-MITOS score.
Analyses of the changes in efficacy endpoints from baseline to month 3 (as inferential analysis)
and from month 3 to month 6 (as descriptive analysis) will be also proposed and further detailed
in the SAP.
·
·
PK Analysis
Respiratory function: changes from baseline to 3 months and from baseline to 6
months will be analysed. Analyses will be further detailed in the SAP.
Bioelectrical analysis: changes from baseline to 3 months and from baseline to 6
months will be analysed for the planned following parameters: phase angle,
Z200/Z5 impedance ratio, skeletal muscle mass, dry mass, and dry mass without
fat. Analyses will be further detailed in the SAP.
Individual plasma concentrations of IFB-088 and IFB-139 (i.e. IFB-088 metabolite) with
corresponding nominal sampling times, will be tabulated for each subject and scheduled sampling
time, together with descriptive statistics. Mean plasma IFB-088 concentrations profiles by cohort
will be presented over time graphically, using blood sampling time (x axis) and concentrations
(y axis) on both linear and semi-log scales.
Derived and observed PK parameters will be evaluated by noncompartmental analysis. The
following parameters will be listed and summarised by cohort, as appropriate:
·
AUC, ng.h/mL,
·
Cmax, ng/mL, with associated Tmax, h,
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·
Terminal or apparent terminal t1/2, h,
·
 Apparent systemic clearance (Cl/F, L/h) and apparent volume of distribution (Vd/F, L) at
steady state, where F is the overall oral bioavailability of IFB-088.
For the calculation of derived PK parameters, concentrations below the lower limit of
quantification (LLOQ) will be assigned a value of zero.
Plasma concentrations of IFB-088 will also be analysed using a population PK modelling approach
to develop a population PK model in patients with ALS. Results of this model will be used to
estimate PK parameters and variability in patients and simulate new dosing schemes (with AUC
and Cmax information) to help choosing the doses for subsequent clinical studies.
Based on our previous PK analyses (Phase I), the developed population pharmacokinetics (popPK)
model with plasma concentrations and urine data of IFB-088 and IFB-139 in patients
(P188_MAD/PK/2019-001) will be evaluated. To evaluate the predictive performance of the
model, goodness-of-fit plots for the predicted and the observed concentration will be first
inspected. Then, prediction error (PE) will be calculated to assess the predictive performance of
the model. Model bias will be determined with the mean prediction error (MPE) and the median
prediction error (MDPE). Model imprecision will be determined with the mean absolute error
(MAE) and the median absolute prediction error (MDAPE). This evaluation will be performed
using a non-linear mixed effects model with NONMEM software (ICON Development Solutions
v7.5). The R software v4.4.1 will be used for goodness-of-fit diagnostics and graphical displays.
Then, this model will be optimised and used to estimate PK parameters and variability in patients
(CL/F, V/F, T1/2 and AUC), and simulated optimal dosing schemes.
A PK/PD (pharmacokinetic/pharmacodynamic) model could be developed according to the
available data. The population PD analysis will be performed with a sequential method using the
final PK model. In a first step, the PK/PD of each PD data will be fitted separately to define the
model more easily then the run simultaneously estimated PD parameters of each PD data.
PK and PD data will be listed and presented in graphical and/or tabular form as appropriate to the
data, and will be summarised descriptively.
Analysis of changes in potential biomarkers
Details of analysis will be provided in the SAP.
Changes in plasma concentration of TDP-43, NfL heavy chain and NfL light chain will be
measured from baseline to 6 months.
Changes in plasma concentration of inflammatory and oxidative stress biomarkers will be
measured from baseline to 3 months, and from baseline to 6 months. All changes will be compared
between both arms.
Correlation of biomarkers with clinical endpoints will be assessed.
QoL endpoint
Change in ALS-AQ40 QoL scores from baseline will be assessed at 6 months and compared
between both arms.
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9.
ETHICS
9.1
STATEMENT
This study will be conducted in accordance with all applicable regulatory requirements including
the principles of the Declaration of Helsinki and in compliance with this protocol, the requirements
of ICH GCP Harmonised Tripartite Guideline Topic E6, Directives 2001/20/EC , 2005/28/ EC of
the European Parliament.
The sponsor is obliged to obtain evidence of the investigator's qualification to perform the clinical
study. Therefore, the investigator has to provide a dated and signed copy of his professional
curriculum vitae (no older than two years and preferably one page-length in English) prior to the
start of the clinical study, including information about his experience and training in conducting
clinical studies according to the guidelines for GCP.
Written approval must be obtained from the IECs and the CAs in each country before the study
can start.
Any modification of the protocol will be made only with the agreement of the sponsor and must
be submitted to the IECs and CAs. No changes in the clinical study protocol will be implemented
until the amendment and revised ICF (if applicable) have received approval from the IECs and the
CAs.
9.2
INDEPENDENT ETHICS COMMITTEE
Prior to the start of the study, the sponsor or investigator will submit the study protocol, patient
information, ICF, and other study-related documents, as required by local regulations, to the
respective regulatory authorities and the responsible IEC for their written approval. The sponsor
or investigator will inform the IEC and regulatory authorities, according to local regulations, about
protocol amendments including any new information that require an ethical reconsideration of the
study protocol.
When required by the IEC or by local regulation, the sponsor or the investigator will submit to the
IEC:
·
Information on AEs that are serious and unexpected and associated with the IMP from the
investigator’s site, as soon as possible,
·
Expedited safety reports from the sponsor, as soon as possible,
·
Periodic summaries on the status of the study, in accordance with the local requirements
and procedures established by the IEC.
9.3
INDEPENDENT DATA MONITORING COMMITTEE
A DSMB without direct involvement in the conduct of the study will be set up to ensure the safety
of the participating patients, the relevance of the study and data integrity. DSMB will be composed
of at least 3 ALS experts. Each DSMB member will be respectively independent from the sponsor
and from the study. DSMB members will monitor safety data and assess patient safety throughout
the duration of the study. All safety data occurring during the trial will be forwarded to the DSMB.
Roles, responsibilities as well as safety monitoring rules and conventions will be reviewed and
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approved by the DSMB at the organisational meeting and included in the DSMB charter. The roles
and responsibilities of the DSMB, their operational procedures, and methods of communication
with the investigators are objects of the separate DSMB charter.
9.4
INFORMED CONSENT
Prior to a patient’s participation in the study, written informed consent must be obtained after the
investigator has fully informed the patient or the patient’s legally accepted representative of all
pertinent aspects of the study. The ICF must be signed and personally dated by the patient or the
patient’s legally accepted representative and by the investigator according to ICH GCP. The patient
or the patient’s legally accepted representative must receive a copy of the signed and dated ICF
and any other written information provided to the patients.
Any change to the information sheet and the consent form constitutes an amendment and must be
submitted for approval to the IEC and the CA.
With the exception of an amendment needed to eliminate hazards to the patients in the study, such
amendments may only be put into practice once written approval from the IEC and the CA has
been obtained.
The new ICF must be signed and personally dated by the patient or the patient’s legally accepted
representative and by the investigator and the patient or the patient’s legally accepted
representative must receive a copy of this signed and dated ICF.
10.
CONTRACT RESEARCH ORGANISATION AND
SUBCONTRACTORS
The following activities have been outsourced from the sponsor:
Keyrus Life Science (KLS)
155 rue Anatole France,
92300 Levallois Perret, France
Phone: +33 1 41 34 10 00
08-Apr-2024
Project Management
Regulatory Affairs
Quality assurance
Randomisation
Clinical operations
Data management
Data review meeting (DRM)
DSMB
Clinical data interchange
standards consortium (CDISC)
Statistics
Medical writing
Clinical trial supply
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STRAGEN Services SAS
19 rue Jacqueline Auriol,
69008 Lyon, France
Phone: +33 4 78 42 95 26
Central laboratories
Pharmacovigilance and safety
PK, crystalluria, biomarkers and
biobank
11.
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA
/ DOCUMENTS
Source data and documents are all information, original records of clinical findings, observations
or other activities in a clinical study necessary for the reconstruction and evaluation of the study.
Examples of these original documents and data records include concomitant medication forms,
laboratory reports, and investigational product accountability records.
According to GCP guidelines, upon request of the CRA, auditor, IEC or regulatory authority, the
investigator must provide direct access to all requested source data / documents.
12.
QUALITY CONTROL AND QUALITY ASSURANCE
12.1
STUDY MONITORING
In accordance with applicable regulations, GCP and CRO standard operating procedures, an
initiation visit will be performed at the investigator centre before any patients are included in the
study. The aim of this visit is to review the protocol and data collection procedures with the study
personnel as well as to provide a reminder of the investigator responsibilities according to ICH
GCP.
During the study, the CRA will regularly contact the centre and will perform on-site monitoring
visits. The extent, nature and frequency of on-site visits will be based on the patient inclusion rate
and will be discussed with the investigator. The aim of these contacts and visits is to check the
progress of the study, review collected study data, conduct source document verification and
identify any issues and address their resolution. This will be done in order to verify that the data
are authentic, accurate and complete, the safety and rights of patients are being protected and the
study is being conducted in accordance with the approved protocol (and any amendments), GCP,
and all applicable regulatory requirements.
The investigator agrees to allow the CRA direct access to all relevant documents and to allocate
his time and the time of the study personnel to discuss any issues.
Upon completion of the study the CRA, with the collaboration of the investigator, will ensure that:
·
All data queries have been finalised,
·
The centres’ study records are complete.
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12.2
AUDIT
To ensure compliance with GCP and all applicable regulatory requirements, the sponsor or a CRO
designated by the sponsor may conduct a quality assurance (QA) audit of the investigator centre.
Regulatory agencies may also conduct regulatory inspections. Such audits or inspections can occur
at any time during or after completion of the study. If an audit or inspection occurs, the investigator
centre agrees to allow the auditor / inspector direct access to all relevant documents and to allocate
his time and the time of the study personnel to the auditor / inspector to discuss findings and any
relevant issues.
13.
CONFIDENTIALITY, DATA HANDLING AND RECORD
KEEPING
13.1
CONFIDENTIALITY
Information regarding patients’ identity obtained as a result of this study is considered confidential
and disclosure to unauthorised individuals is prohibited. Patients will not be identified by their
names or dates of birth on the eCRF or other study documentation submitted to the sponsor; instead
patients will be given a unique identification number as soon as they have signed their ICF. For
safety reasons, the investigator will maintain a patient identification log with the name and contact
details of each patient. This log and the signed consent forms will be kept in strict confidence by
the investigator.
13.2
DATA HANDLING
All clinical data will be reported by the investigator or authorised designee on the eCRF. The eCRF
is specifically designed for this study and developed by KLS data management department. A
unique number will identify each patient on the eCRF (see Section 3.8). The investigator will
ensure that all data are entered after the evaluation has occurred, in accordance with source
documents.
In case of missing values, out of range values or data inconsistencies, queries will be generated
and submitted to the investigator site for resolution. Coding of AEs will be performed using the
MedDRA and coding of previous and concomitant treatments will be performed using the world
health organisation (WHO) drug dictionary enhanced.
13.3
RECORD KEEPING
13.3.1
Investigator
Following closure of the study, the investigators must archive, in a safe and secure location, all
study records including patient medical files, original ICFs, source documents, copies of the
eCRFs, copies of the study product accountability forms, copies of the regulatory authorities’
approval and all correspondence. Investigators will retain all study documentation for the
maximum period of time required by local requirements.
The records must be maintained in a way to allow easy and timely retrieval when needed e.g. for
an audit, inspection or any subsequent review of data in conjunction with assessment of the facility,
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supporting systems and staff. Where permitted by local laws and regulations, some or all of these
records can be maintained in a format other than hard copy e.g. microfiche, scanned, electronic,
however, caution needs to be exercised before such action is taken. The investigator must assure
that all reproductions are legible, are a true and accurate copy of the original and meet accessibility
and retrieval standards (a hard copy must be regenerated if required). Furthermore, the investigator
must ensure that there is an acceptable back-up of these reproductions and that an acceptable
quality control process exists for making these reproductions.
The investigator agrees to provide direct access to source documents during monitoring visits.
The investigator must notify the sponsor of any changes in the archiving arrangements, including,
but not limited to: archival at an off-site facility and transfer of ownership of the records in the
event the investigator leaves the site.
13.3.2
Sponsor
The following documents are to be archived by the sponsor in accordance with GCP and applicable
regulatory requirements:
·
Final version of the protocol,
·
Any protocol amendments,
·
Original eCRFs and queries,
·
IEC and CA approval forms,
·
All correspondence related to the study,
·
The investigator’s and any co-investigators’ curriculum vitae,
·
All other documents generated during the study.
All of the above documents must be archived in a room specifically designated for this purpose,
access to which is controlled by the person responsible for archiving.
14.
INSURANCE AND FINANCES
14.1
INSURANCE
The sponsor, InFlectis BioScience, certifies that a medical insurance policy has been taken out,
which covers the liability of the investigator in case of damage or injury resulting from this study,
in accordance with Articles 3.2 and 6.3 of Directive 2001 / 20 / EC of the European Parliament.
This insurance does not relieve the investigators of any obligation to maintain their own liability
insurance policy as required by applicable law.
14.2
FINANCES
Contracts will be written up between the sponsor / CRO and the sites. A site-specific agreement
will be signed by the investigators and the sponsor.
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14.3
PATIENT PAYMENTS AND EXPENSES
Patients will be reimbursed for all expenses in relation to their participation to the study. Patients
will not receive a compensation for their participation.
15.
REPORT AND PUBLICATION POLICY
15.1
REPORT
After completion of the study, the results will be reported in a CSR according to the ICH-E3 note
for guidance on structure and content of CSRs. The sponsor will send a summary of this CSR to
the regulatory authorities within one year after the end of the trial.
15.2
DISCLOSURE OF DATA
No information provided by InFlectis BioScience to the investigators for the purposes of
performing the study, will be published, or passed on to a third party, without prior written
approval by InFlectis BioScience.
The investigators will have full access to all study data and will take complete responsibility for
the integrity of the data and the relevance of the data analysis and reporting.
After regulatory clearance, the study will be registered by the sponsor or an appointed CRO in the
ClinTrials.gov database. The principal investigator or anyone else working on the study will
submit all proposed publications, papers, abstracts, other written materials or an outline of any
proposed oral presentation related to the study to InFlectis BioScience at least one month prior to
(i) submission of such written materials for publication, or (ii) any proposed oral disclosure to a
third party. InFlectis BioScience shall have the right to comment on such written material/outline
and to take any necessary action to protect its intellectual property; the principal investigator, in
determining the final form of disclosure, shall consider such comments in good faith.
Notwithstanding any of the above, the principal investigator or anyone else working on the study
may not include any confidential information unrelated to the study in any such publication or
disclosure.
The investigator will provide InFlectis BioScience with complete test results and all data derived
from the study in accordance with the protocol.
Only InFlectis BioScience and its authorised contractor may make information obtained during
the study available to regulatory agencies, except as required by regulation.
15.3
PUBLICATION
The sponsor commits to communicating, and otherwise making available for public disclosure, the
results of the clinical study, including publication of a paper in a scientific journal, abstract
submission with a poster or oral presentation at a scientific meeting, or disclosure by other means.
However, the sponsor reserves the right to defer the release of data until specified milestones are
reached, for example when the CSR is available.
Study results will be published as manuscripts in peer-reviewed scientific journals, in an objective,
accurate, balanced and complete manner.
Authorship Policy
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Authorship of any public disclosure must be in accordance with the “Recommendations for the
conduct, reporting, editing, and publication of scholarly work in medical journals” of the
international committee of medical journal editors (ICMJE, [46]), i.e. fulfilling the following 4
criteria:
·
Substantial contributions to the conception or design of the work; or the acquisition,
analysis, or interpretation of data for the work; and,
·
Drafting the work or revising it critically for important intellectual content; and,
·
Final approval of the version to be published; and,
·
Agreement to be accountable for all aspects of the work in ensuring that questions related
to the accuracy or integrity of any part of the work are appropriately investigated and
resolved.
Authors will be determined at the end of the study according to their substantial contributions.
Those who do not meet all 4 criteria will be acknowledged as contributors.
As far as they fulfil their responsibilities up to the end of the study and meet the ICMJE criteria,
the principal investigator and co-principal investigator will have the first and last authorship
position respectively.
16.
REFERENCE LIST
1.
Chiò A, Logroscino G, Traynor BJ et al. Global Epidemiology of Amyotrophic Lateral
Sclerosis: A Systematic Review of the Published Literature. Neuroepidemiology 2013;
41(2):118–130.
2.
Logroscino G, Traynor BJ, Hardiman O et al. Incidence of Amyotrophic Lateral Sclerosis in
Europe. J. Neurol. Neurosurg. Psychiatry 2010; 81(4):385.
3.
Al-Chalabi A, Hardiman O, Kiernan M et al. Amyotrophic lateral sclerosis: moving towards
a new classification system. Lancet. Neurol. 2016; 15(11):1182–1194.
4.
Longinetti E, Fang F. Epidemiology of amyotrophic lateral sclerosis: an update of recent
literature. Curr. Opin. Neurol. 2019; 32(5):771–776.
5.
Strong MJ, Abrahams S, Goldstein LH et al. Amyotrophic lateral sclerosis - frontotemporal
spectrum disorder (ALS-FTSD): Revised diagnostic criteria.
6.
Crockford C, Newton J, Lonergan K et al. ALS-specific cognitive and behavior changes
associated with advancing disease stage in ALS. Neurology 2018; 91(15):e1370–e1380.
7.
Miller RG, Mitchell JD, Moore DH, Group CN. Riluzole for amyotrophic lateral sclerosis
(ALS)/motor neuron disease (MND). Cochrane Database Syst. Rev. 2012.
8.
Cho H, Shukla S. Role of Edaravone as a Treatment Option for Patients with Amyotrophic
Lateral Sclerosis. Pharmaceuticals 2021; 14(1):1–14.
9.
Mandrioli J, Faglioni P, Nichelli P, Sola P. Amyotrophic lateral sclerosis: prognostic
indicators of survival. Amyotroph Lateral Scler. 2006 Dec;7(4):211-20.
10.
Renton AE, Chiò A, Traynor BJ. State of play in amyotrophic lateral sclerosis genetics. Nat.
Neurosci. 2014; 17(1):17.
11.
Couratier P, Lautrette G, Luna JA, Corcia P. Phenotypic variability in amyotrophic lateral
sclerosis. Rev. Neurol. (Paris). 2021; 177(5):536–543.
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12.
Piao Y-S, Wakabayashi K, Kakita A et al. Neuropathology with Clinical Correlations of
Sporadic Amyotrophic Lateral Sclerosis: 102 Autopsy Cases Examined Between 1962 and
2000. Brain Pathol. 2003; 13(1):10–22.
13.
Braak H, Brettschneider J, Ludolph AC et al. Amyotrophic lateral sclerosis—a model of
corticofugal axonal spread. Nat. Rev. Neurol. 2013; 9(12):708.
14.
Brettschneider J, Tredici K Del, Toledo JB et al. Stages of pTDP-43 pathology in
amyotrophic lateral sclerosis. Ann. Neurol. 2013; 74(1):20–38.
15.
Yerbury J, Farrawell N, McAlary L. Proteome Homeostasis Dysfunction: A Unifying
Principle in ALS Pathogenesis. Trends Neurosci. 2020; 43(5):274–284.
16.
Matus S, Valenzuela V, Medinas DB, Hetz C. ER dysfunction and protein folding stress in
ALS. Int. J. Cell Biol. 2013.
17.
Dafinca R, Barbagallo P, Talbot K. The Role of Mitochondrial Dysfunction and ER Stress
in TDP-43 and C9ORF72 ALS. Front. Cell. Neurosci. 2021.
18.
Turner B, Atkin J. ER stress and UPR in familial amyotrophic lateral sclerosis. Curr. Mol.
Med. 2006; 6(1):79–86.
19.
Ilieva E V., Ayala V, Jové M et al. Oxidative and endoplasmic reticulum stress interplay in
sporadic amyotrophic lateral sclerosis. Brain 2007; 130(12):3111–3123.
20.
Hetz C, Chevet E, Oakes S. Proteostasis control by the unfolded protein response. Nat. Cell
Biol. 2015; 17(7):829–838.
21.
Ito Y, Yamada M, Tanaka H et al. Involvement of CHOP, an ER-stress apoptotic mediator,
in both human sporadic ALS and ALS model mice. Neurobiol. Dis. 2009; 36(3):470–476.
22.
Tsaytler P, Harding HP, Ron D, Bertolotti A. Selective Inhibition of a Regulatory Subunit
of Protein Phosphatase 1 Restores Proteostasis. Science (80-. ). 2011; 332(6025):91–94.
23.
Vaccaro A, Patten SA, Aggad D et al. Pharmacological reduction of ER stress protects
against TDP-43 neuronal toxicity in vivo. Neurobiol. Dis. 2013; 55:64–75.
24.
Wang L, Popko B, Tixier E, Roos RP. Guanabenz, which enhances the unfolded protein
response, ameliorates mutant SOD1-induced amyotrophic lateral sclerosis. Neurobiol. Dis.
2014; 71:317–324.
25.
Jiang HQ, Ren M, Jiang HZ et al. Guanabenz delays the onset of disease symptoms, extends
lifespan, improves motor performance and attenuates motor neuron loss in the SOD1 G93A
mouse model of amyotrophic lateral sclerosis. Neuroscience 2014; 277:132–138.
26.
Dalla Bella E, Bersano E, Antonini G et al. The unfolded protein response in amyotrophic
later sclerosis: results of a phase 2 trial. Brain 2021.
27.
Das I, Krzyzosiak A, Schneider K et al. Preventing proteostasis diseases by selective
inhibition of a phosphatase regulatory subunit. Science 2015; 348(6231):239.
28.
Inoue-Shibui A, Kato M, Suzuki N et al. Interstitial pneumonia and other adverse events in
riluzole-administered amyotrophic lateral sclerosis patients: a retrospective observational
study.
29.
Brooks BR, Miller RG, Swash M, Munsat TL. El Escorial revisited: Revised criteria for the
diagnosis of amyotrophic lateral sclerosis.
30.
Kaufmann P, Levy G, Montes J et al. Excellent inter-rater, intra-rater, and telephone-
administered reliability of the ALSFRS-R in a multicenter clinical trial. Amyotroph. Lateral
Scler. 2007; 8(1):42–46.
31.
Maier A, Holm T, Wicks P et al. Online assessment of ALS functional rating scale compares
well to in-clinic evaluation: a prospective trial. Amyotroph. Lateral Scler. 2012; 13(2):210–
216.
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32.
Cedarbaum J, Stambler N, Malta E et al. The ALSFRS-R: a revised ALS functional rating
scale that incorporates assessments of respiratory function. BDNF ALS Study Group (Phase
III). J. Neurol. Sci. 1999; 169(1–2):13–21.
33.
Castrillo-Viguera C, Grasso D, Simpson E et al. Clinical significance in the change of decline
in ALSFRS-R. Amyotroph. Lateral Scler. 2010; 11(1–2):178–180.
34.
Chiò A, Hammond ER, Mora G et al. Development and evaluation of a clinical staging
system for amyotrophic lateral sclerosis. J. Neurol. Neurosurg. Psychiatry 2015; 86(1):38–
44.
35.
Tramacere I, Dalla Bella E, Chiò A et al. The MITOS system predicts long-term survival in
amyotrophic lateral sclerosis. J. Neurol. Neurosurg. Psychiatry 2015; 86(11):1180–1185.
36.
Roche J, Rojas-Garcia R, Scott K et al. A proposed staging system for amyotrophic lateral
sclerosis. Brain 2012; 135(Pt 3):847–852.
37.
Balendra R, Khleifat A Al, Fang T, Al-Chalabi A. A standard operating procedure for King’s
ALS clinical staging. Amyotroph. Lateral Scler. Frontotemporal Degener. 2019; 20(3–
4):159.
38.
Fang T, Khleifat A Al, Stahl DR et al. Comparison of the King’s and MiToS staging systems
for ALS. Amyotroph. Lateral Scler. Frontotemporal Degener. 2017; 18(3–4):227.
39.
Lechtzin N, Cudkowicz ME, Carvalho M de et al. Respiratory measures in amyotrophic
lateral sclerosis.
40.
Paganoni S, Cudkowicz M, Berry JD. Outcome measures in amyotrophic lateral sclerosis
clinical trials. Clin. Investig. (Lond). 2014; 4(7):605.
41.
Manera U, Torrieri MC, Moglia C et al. The role of arterial blood gas analysis (ABG) in
amyotrophic lateral sclerosis respiratory monitoring. J. Neurol. Neurosurg. Psychiatry 2020;
91(9):999–1000.
42.
Yamamoto T, Langham RG, Ronco P et al. Towards standard protocols and guidelines for
urine proteomics: A report on the Human Kidney and Urine Proteome Project (HKUPP)
symposium and workshop - 6 October 2007, Seoul, Korea and 1 November 2007, San
Francisco, CA, USA. Proteomics 2008; 8(11):2156–2159.
43.
Jenkinson C, Levvy G, Fitzpatrick R, Garratt A. The amyotrophic lateral sclerosis
assessment questionnaire (ALSAQ-40): tests of data quality, score reliability and response
rate in a survey of patients. J. Neurol. Sci. 2000; 180(1):94–100.
44.
 Summary
of
product
characteristics
Rilutek,
INN-riluzole.
[https://www.ema.europa.eu/en/documents/product-information/rilutek-epar-product-
information_en.pdf].
45.
Ge M, Durham LK, Meyer RD et al. Covariate-Adjusted Difference in Proportions from
Clinical Trials Using Logistic Regression and Weighted Risk Differences. Ther. Innov.
Regul. Sci. 2011; 45(4):481–493.
46.
ICMJE | Recommendations. [http://www.icmje.org/recommendations/].
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17.
APPENDICES
17.1
SCALES AND QUESTIONNAIRES
17.1.1
ALSFRS-R
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ALS Functional Rating Scale Revised (ALS-FRS-R)
Date:………………………………….Name patient:………………………………………………Date of Birth:……………………………………
Patient’s number……………………………………………………………………………………..Right-/left-handed
Item 1: SPEECH
4
3  2
1  0
Normal speech process
Detectable speech disturbance
Intelligible with repeating
Speech combined with non-vocal communication
Loss of useful speech
Item 2: SALIVATION
4 
Normal
3 
Slight but definite excess of saliva in mouth; may have nighttime drooling
2 
Moderately excessive saliva; may have minimal drooling (during the day)
1 
Marked excess of saliva with some drooling
0 
Marked drooling; requires constant tissue or handkerchief
Item 3: SWALLOWING
4 
Normal eating habits
3 
Early eating problems – occasional choking
2 
Dietary consistency changes
1 
Needs supplement tube feeding
0 
NPO (exclusively parenteral or enteral feeding)
Item 4: HANDWRITING
4 
Normal
3 
Slow or sloppy: all words are legible
2 
Not all words are legible
1 
Able to grip pen, but unable to write
0 
Unable to grip pen
Item 5a: CUTTING FOOD AND HANDLING UTENSILS
Patients without gastrostomy Æ Use 5b if >50% is through g-tube
4 
Normal
3 
Somewhat slow and clumsy, but no help needed
2 
Can cut most foods (>50%), although slow and clumsy; some help needed
1 
Food must be cut by someone, but can still feed slowly
0 
Needs to be fed
Item 5b: CUTTING FOOD AND HANDLING UTENSILS
Patients with gastrostomy Æ 5b option is used if the patient has a gastrostomy and only if it is the primary
method (more than 50%) of eating .
4 
Normal
3 
Clumsy, but able to perform all manipulations independently
2 
Some help needed with closures and fasteners
1 
Provides minimal assistance to caregiver
0 
Unable to perform any aspect of task
ALS Functional Rating Scale Revised (ALS-FRS-R). Version: May 2015
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Item 6: DRESSING AND HYGIENE
4            Normal function
3            Independent and complete self-care with effort or decreased efficiency 2
Intermittent assistance or substitute methods
1            Needs attendant for self-care 0
Total dependence
Item 7: TURNING IN BED AND ADJUSTING BED CLOTHES
4            Normal function
3            Somewhat slow and clumsy, but no help needed
2            Can turn alone, or adjust sheets, but with great difficulty 1
Can initiate, but not turn or adjust sheets alone
0            Helpless
Item 8: WALKING
4            Normal
3            Early ambulation difficulties 2
Walks with assistance
1            Non-ambulatory functional movement 0
No purposeful leg movement
Item 9: CLIMBING STAIRS
4            Normal 3
Slow
2            Mild unsteadiness or fatigue 1
Needs assistance
0            Cannot do
Item 10: DYSPNEA
4            None
3            Occurs when walking
2            Occurs with one or more of the following: eating, bathing, dressing (ADL) 1
Occurs at rest: difficulty breathing when either sitting or lying
0            Significant difficulty: considering using mechanical respiratory support
Item 11: ORTHOPNEA
4            None
3            Some difficulty sleeping at night due to shortness of breath, does not routinely use more than
two pillows
2            Needs extra pillows in order to sleep (more than two) 1
Can only sleep sitting up
0            Unable to sleep without mechanical assistance
Item 12: RESPIRATORY INSUFFICIENCY
4            None
3            Intermittent use of BiPAP
2            Continuous use of BiPAP during the night
1            Continuous use of BiPAP during day & night
0            Invasive mechanical ventilation by intubation or tracheostomy
Interviewer’s name………………………………………………………………………………………………………………………………………
ALS Functional Rating Scale Revised (ALS-FRS-R). Version: May 2015
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17.1.2
ALS-MITOS
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ALS Milano-Torino Staging (ALS-MITOS)
Date:………………………………….Name patient:………………………………………………
Date of Birth:……………………………………
Patient’s number……………………………………………………………………………………..
ALSFRS domain
Movement
(walking/self-care)†
Swallowing
Communicating†
Item
8
Walking
OR
6
Dressing
and hygiene
3
Swallowing
1
Speech
AND
Score
4 Normal
3 Early ambulation difficulties
2 Walks with assistance
1 Non-ambulatory functional movement only
0 No purposeful leg movement
4 Normal function
3 Independent and complete self-care with effort
or decreased efficiency
2 Intermittent assistance or substitute methods
1 Needs attendant for self-care
0 Total dependence
4 Normal eating habits
3 Early eating problems; occasional choking
2 Dietary consistency changes
1 Needs supplemental tube feeding
0 NPO (exclusively parenteral or enteral feeding)
4 Normal speech processes
3 Detectable speech with disturbances
2 Intelligible with repeating
1 Speech combined with non-vocal
communication
0 Loss of useful speech
Functional
score*
0
1
0
1
0
1
0
1
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Breathing†
ALS-MITOS
4
Handwriting
10
Dyspnea
OR
12
Respiratory
insufficiency
Stage
0
1
2
3
4
5
4 Normal
0
3 Slow or sloppy; all words are legible
2 Not all words are legible
1 Able to grip pen but unable to write
1
0 Unable to grip pen
4 None
0
3 Occurs when walking
2 Occurs with one or more of: eating, bathing,
dressing
1 Occurs at rest, difficulty breathing when either
sitting or lying
1
0 Significant difficulty, considering using
mechanical respiratory support
4 None
0
3 Intermittent use of NIPPV
2 Continuous use of NIPPV during the night
1
1 Continuous use of NIPPV during the night and
day
0 Invasive mechanical ventilation by intubation or
tracheostomy
Functional domains lost
None
1 domain
2 domains
3 domains
4 domains
Death
*Staging determined by the sum of functional score of 1 for each domain.
†Where two items were used, scoring was based on either or both item scores as
indicated.
ALFSRS, Amyotrophic Lateral Sclerosis Functional Rating Scale; ALS-MITOS, Amyotrophic
Lateral Sclerosis Milano-Torino Staging; NIPPV, nasal intermittent positive pressure ventilation;
NPO, nothing to mouth.
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Chiò A, et al. J Neurol Neurosurg Psychiatry 2013;0:1–7. doi:10.1136/jnnp-2013-306589
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17.1.3
King’s College scale
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Affix Hospital Sticker Here
KING’S ALS STAGING FORM
Or Enter Patient Details
Date: ___________
Tester’s name: _______________
Bulbar region:
     Unaffected
     Function affected (e.g. slurred speech, slowing difficulty, or hypophonia)
     Affected on examination only (accepted signs: tongue atrophy fasciculation,
slowness of movement)
     Affected on reflex examination only (accepted sign: pathologically brisk jaw jerks only)
Upper limbs:
     Unaffected
     Function affected (e.g. difficulty with keys, doorknobs, zips, bags)
     Affected on examination only (accepted sign: wasting of the first dorsal interossei)
     Affected on reflex examination only (accepted signs: the presence of pectoral
reflexes or Hoffman’s sign)
Lower limbs:
     Unaffected
     Function affected e.g. difficulty walking, falls, cramps etc.
     Affected on examination only (accepted signs: gait stiffness or foot drop)
     Affected on reflex examination only (accepted signs: crossed adductor reflexes,
pathologically brisk patellar reflexes or ankle clonus)
Weight (in Kg)
an estimate is acceptable if actual weight is not known or measurable
Current
Baseline Weight
RIG needed/ in-situ: Yes
No
Respiratory symptoms (exertional dyspnea, orthopnoea or excessive daytime sleepiness):
Yes
No
Respiratory function Please complete what is available
SNIP (cm H2O)
Recent SNIP in last 3 months:
FVC
Pulse Oximetry
SpO2
pCO2
NIV needed/used: Yes
No
NOTE: If pulse oximetry is the only measure used to test respiratory function AND SpO2 is
≤94% AND pCO2 <6kPa then arrange for the patient to have overnight oximetry
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Does patient fulfil any of the criteria for
advanced disease requiring intervention?
1. RIG needed/ in-situ
Y     N
2. NIV needed/used
Y
N
3. Weight loss more than 10% of baseline
Y     N
4. SNIP < 40cm H20 or a decrease > 10cm H20 over 3 months     Y     N
5. Patient has respiratory symptoms AND
SNIP is < 65cm H20 (for men) or < 55cm H20 (for women). Y     N
6. FVC: < 50% of predicted FVC.     Y     N
7. Patient has respiratory symptoms AND FVC < 80% of predicted FVC Y     N
8. SpO2 on oximetry is ≤94% AND either
      pCO2 >6kPa OR     Y     N
      Overnight oximetry shows ≥5 dips/hours below 80%
Y     N
NO to all above
How many regions
(Bulbar, Upper limb, lower
YES to any of above
Stage 4
limb)
Involvement
are involved?
Stage
Patient’s KCL Stage
One region involved
1
Two regions involved
2
Three regions involved
3
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17.1.4
ALSAQ-40
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ALSAQ-40
Please complete this questionnaire as soon as possible. If
you have any difficulties filling in the questionnaire by yourself,
please get someone else to help you with it. However it is your
responses that we are interested in.
The questionnaire consists of a number of statements about
difficulties that you may have experienced during the last 2
weeks. There are no right or wrong answers: your first response is
likely to be the most accurate for you. Please tick the box which
best describes your own experience or feelings.
Please try to answer every question even though some may
seem rather similar to others, or may not seem relevant to you.
All the information you give will be treated in the strictest
confidence.
The following statements all refer to difficulties that you
may have had during the last 2 weeks.
Please indicate, by ticking the appropriate box, how often
the following statements have been true for you.
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The following statements all refer to certain difficulties that you may have
had during the last 2 weeks. Please indicate, by ticking the appropriate box,
how often the following statements have been true for you.
If you cannot walk at all
please tick Always/cannot walk at all.
How often during the last 2 weeks
have the following been true?
Please tick one box for each question
Never
Rarely
Some-
Often
times
Always
or
cannot
walk at
all
1. I have found it
difficult to walk short
distances, e.g. around
the house.
2. I have fallen over
whilst walking.
3. I have stumbled or
tripped whilst
walking.
4. I have lost my
balance whilst
walking.
5. I have had to
concentrate whilst
walking.
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
  
Please make sure that you have ticked one box for each question
before going on to the next page.
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The following statements all refer to certain difficulties that you may have
had during the last 2 weeks. Please indicate, by ticking the appropriate box,
how often the following statements have been true for you.
If you cannot do the activity at all
please tick Always/cannot do at all.
How often during the last 2 weeks
have the following been true?
Please tick one box for each question
Never
Rarely
Some-
Often
times
Always
or
cannot
do at
all
6. Walking has tired
me out.
7. I have had pains in
my legs whilst
walking.
8. I have found it
difficult to go up and
down the stairs.
9. I have found it
difficult to stand up.
10. I have found it
difficult to get myself
up out of chairs.
 
 
  
 
 
  
 
 
  
 
 
  
 
 
  
Please make sure that you have ticked one box for each question
before going on to the next page.
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The following statements all refer to certain difficulties that you may have
had during the last 2 weeks. Please indicate, by ticking the appropriate box,
how often the following statements have been true for you.
If you cannot do the activity at all
please tick Always/cannot do at all.
How often during the last 2 weeks
have the following been true?
Please tick one box for each question
Never
Rarely
Some-
Often
times
Always
or
cannot
do at
all
11. I have had
difficulty using my
arms and hands.
12. I have found
turning and moving in
bed difficult.
13. I have found
picking things up
difficult.
14. I have found
holding books or
newspapers, or turning
pages, difficult.
15. I have had
difficulty writing
clearly.
 
 
  
 
 
  
 
 
  
 
 
  
 
 
  
Please make sure that you have ticked one box for each question
before going on to the next page.
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The following statements all refer to certain difficulties that you may have
had during the last 2 weeks. Please indicate, by ticking the appropriate box,
how often the following statements have been true for you.
If you cannot do the activity at all
please tick Always/cannot do at all.
How often during the last 2 weeks
have the following been true?
Please tick one box for each question
Never
Rarely
Some-
Often
times
Always
or
cannot
do at
all
16. I have found it
difficult to do jobs
around the house.
17. I have found it
difficult to feed
myself.
18. I have had
difficulty combing my
hair or cleaning my
teeth.
19. I have had
difficulty getting
dressed.
20. I have had
difficulty washing at
the hand basin.
 
 
  
 
 
  
 
 
  
 
 
  
 
 
  
Please make sure that you have ticked one box for each question
before going on to the next page.
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The following statements all refer to certain difficulties that you may have
had during the last 2 weeks. Please indicate, by ticking the appropriate box,
how often the following statements have been true for you.
If you cannot do the activity at all
please tick Always/cannot do at all.
How often during the last 2 weeks
have the following been true?
Please tick one box for each question
Never
Rarely
Some-
Often
times
Always
or
cannot
do at
all
21. I have had
difficulty swallowing.
22. I have had
difficulty eating solid
food.
23. I have found it
difficult to drink
liquids.
24. I have found it
difficult to participate
in conversations.
25. I have felt that my
speech has not been
easy to understand.
 
 
  
 
 
  
 
 
  
 
 
  
 
 
  
Please make sure that you have ticked one box for each question
before going on to the next page.
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The following statements all refer to certain difficulties that you may have
had during the last 2 weeks. Please indicate, by ticking the appropriate box,
how often the following statements have been true for you.
If you cannot do the activity at all
please tick Always/cannot do at all.
How often during the last 2 weeks
have the following been true?
Please tick one box for each question
Never
Rarely
Some-
Often
times
Always
or
cannot
do at
all
26. I have slurred or
stuttered whilst
speaking.
27. I have had to talk
very slowly.
28. I have talked less
than I used to do.
29. I have been
frustrated by my
speech.
30. I have felt self-
conscious about my
speech.
 
 
  
 
 
  
 
 
  
 
 
  
 
 
  
Please make sure that you have ticked one box for each question
before going on to the next page.
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The following statements all refer to certain difficulties that you may have
had during the last 2 weeks. Please indicate, by ticking the appropriate box,
how often the following statements have been true for you.
How often during the last 2 weeks
have the following been true?
Please tick one box for each question
Never
Rarely
Some-
Often
Always
times
31. I have felt lonely.
32. I have been bored.
33. I have felt
embarrassed in social
situations.
34. I have felt
hopeless about the
future.
35. I have worried
that I am a burden to
other people.
 
 
  
 
 
  
 
 
  
 
 
  
 
 
  
Please make sure that you have ticked one box for each question
before going on to the next page.
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The following statements all refer to certain difficulties that you may have
had during the last 2 weeks. Please indicate, by ticking the appropriate box,
how often the following statements have been true for you.
How often during the last 2 weeks
have the following been true?
Please tick one box for each question
Never
Rarely
Some-
Often
Always
times
36. I have wondered
why I keep going.
37. I have felt angry
because of the
disease.
38. I have felt
depressed.
39. I have worried
about how the disease
will affect me in the
future.
40. I have felt as if I
have no freedom.
 
 
  
 
 
  
 
 
  
 
 
  
 
 
  
Please make sure that you have ticked one box for each question.
Thank you for completing this questionnaire.
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17.1.5
C-SSRS
·
C-SSRS Lifetime
·
C-SSRS Since Last Visit
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COLUMBIA-SUICIDE SEVERITY
RATING SCALE
(C-SSRS)
Lifetime Recent
Version 1/14/09 m9/12/17
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; Zelazny, J.;
Burke, A.; Oquendo, M.; Mann, J.
Disclaimer:
This scale is intended to be used by individuals who have received training in its administration. The questions contained in
the Columbia-Suicide Severity Rating Scale are suggested probes. Ultimately, the determination of the presence of suicidal
ideation or behavior depends on the judgment of the individual administering the scale.
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia Suicide History Form,
developed by John Mann, MD and Maria Oquendo, MD, Conte Center for the Neuroscience of Mental Disorders
(CCNMD), New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032. (Oquendo M. A.,
Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of research instruments. In M.B. First
[Ed.] Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.)
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 1051 Riverside Drive, New
York, New York, 10032; inquiries and training requirements contact posnerk@nyspi.columbia.edu
© 2008 The Research Foundation for Mental Hygiene, Inc.
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SUICIDAL IDEATION
Ask questions 1 and 2. If both are negative, proceed to “Suicidal Behavior” section. If the answer to
question 2 is “yes”, ask questions 3, 4 and 5. If the answer to question 1 and/or 2 is “yes”, complete
“Intensity of Ideation” section below.
1. Wish to be Dead
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up.
Have you wished you were dead or wished you could go to sleep and not wake up?
If yes, describe:
Lifetime: Time
He/She Felt
Most Suicidal
Yes        No
□     □
Past 1
month
Yes      No
□ □
2. Non-Specific Active Suicidal Thoughts
General non-specific thoughts of wanting to end one’s life/die by suicide (e.g., “I’ve thought about killing myself”) without thoughts of
ways to kill oneself/associated methods, intent, or plan during the assessment period.
Have you actually had any thoughts of killing yourself?
If yes, describe:
3. Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is different than a
specific plan with time, place or method details worked out (e.g., thought of method to kill self but not a specific plan). Includes person
who would say, “I thought about taking an overdose but I never made a specific plan as to when, where or how I would actually do
it…and I would never go through with it.”
Have you been thinking about how you might do this?
If yes, describe:
4. Active Suicidal Ideation with Some Intent to Act, without Specific Plan
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as opposed to “I have the
thoughts but I definitely will not do anything about them.”
Have you had these thoughts and had some intention of acting on them?
If yes, describe:
5. Active Suicidal Ideation with Specific Plan and Intent
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it out.
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan?
If yes, describe:
INTENSITY OF IDEATION
The following features should be rated with respect to the most severe type of ideation (i.e., 1-5 from above, with 1 being
the least severe and 5 being the most severe). Ask about time he/she was feeling the most suicidal.
Yes        No           Yes      No
□     □       □ □
Yes       No            Yes      No
□     □       □ □
Yes       No             Yes      No
□     □        □ □
Yes        No            Yes      No
□     □       □ □
Lifetime - Most Severe Ideation: _______
Type # (1-5)
Recent - Most Severe Ideation: _______
Type # (1-5)
________________________________________
Description of Ideation
________________________________________
Description of Ideation
Most
Most
Severe              Severe
Frequency
How many times have you had these thoughts?
(1) Less than once a week     (2) Once a week (3) 2-5 times in week     (4) Daily or almost daily     (5) Many times each day
Duration
When you have the thoughts how long do they last?
(1) Fleeting - few seconds or minutes
(4) 4-8 hours/most of day
(2) Less than 1 hour/some of the time
(5) More than 8 hours/persistent or continuous
(3) 1-4 hours/a lot of time
Controllability
Could/can you stop thinking about killing yourself or wanting to die if you want to?
(1) Easily able to control thoughts
(4) Can control thoughts with a lot of difficulty
(2) Can control thoughts with little difficulty
(5) Unable to control thoughts
(3) Can control thoughts with some difficulty
(0) Does not attempt to control thoughts
Deterrents
Are there things - anyone or anything (e.g., family, religion, pain of death) - that stopped you from wanting to
die or acting on thoughts of suicide?
(1) Deterrents definitely stopped you from attempting suicide
(4) Deterrents most likely did not stop you
(2) Deterrents probably stopped you
(5) Deterrents definitely did not stop you
(3) Uncertain that deterrents stopped you
(0) Does not apply
Reasons for Ideation
What sort of reasons did you have for thinking about wanting to die or killing yourself? Was it to end the pain
or stop the way you were feeling (in other words you couldn’t go on living with this pain or how you were
feeling) or was it to get attention, revenge or a reaction from others? Or both?
(1) Completely to get attention, revenge or a reaction from others
(4) Mostly to end or stop the pain (you couldn’t go on
(2) Mostly to get attention, revenge or a reaction from others                       living with the pain or how you were feeling)
(3) Equally to get attention, revenge or a reaction from others
(5) Completely to end or stop the pain (you couldn’t go on
and to end/stop the pain                                                                              living with the pain or how you were feeling)
(0) Does not apply
____
____
____
____
____
____
____
____
____
____
© 2008 Research Foundation for Mental Hygiene, Inc.
C-SSRS—Lifetime Recent (Version 1/14/09)
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SUICIDAL BEHAVIOR
(Check all that apply, so long as these are separate events; must ask about all types)
Actual Attempt:
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought of as method to kill
oneself. Intent does not have to be 100%. If there is any intent/desire to die associated with the act, then it can be considered an actual suicide
attempt. There does not have to be any injury or harm, just the potential for injury or harm. If person pulls trigger while gun is in
mouth but gun is broken so no injury results, this is considered an attempt.
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or circumstances. For example, a
highly lethal act that is clearly not an accident so no other intent but suicide can be inferred (e.g., gunshot to head, jumping from window of a
high floor/story). Also, if someone denies intent to die, but they thought that what they did could be lethal, intent may be inferred.
Have you made a suicide attempt?
Have you done anything to harm yourself?
Have you done anything dangerous where you could have died?
What did you do?
Did you______ as a way to end your life?
Did you want to die (even a little) when you_____?
Were you trying to end your life when you _____?
Or Did you think it was possible you could have died from_____?
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, feel better,
get sympathy, or get something else to happen)? (Self-Injurious Behavior without suicidal intent)
If yes, describe:
Has subject engaged in Non-Suicidal Self-Injurious Behavior?
Interrupted Attempt:
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not for that, actual attempt would
have occurred).
Overdose: Person has pills in hand but is stopped from ingesting. Once they ingest any pills, this becomes an attempt rather than an interrupted
attempt. Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow prevented from pulling trigger. Once
they pull the trigger, even if the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and taken down from ledge.
Hanging: Person has noose around neck but has not yet started to hang - is stopped from doing so.
Has there been a time when you started to do something to end your life but someone or something stopped you before
you actually did anything?
If yes, describe:
Aborted or Self-Interrupted Attempt:
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have engaged in any self-
destructive behavior. Examples are similar to interrupted attempts, except that the individual stops him/herself, instead of being stopped by
something else.
Has there been a time when you started to do something to try to end your life but you stopped yourself before you
actually did anything?
If yes, describe:
Preparatory Acts or Behavior:
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or thought, such as
assembling a specific method (e.g., buying pills, purchasing a gun) or preparing for one’s death by suicide (e.g., giving things away, writing a
suicide note).
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such as collecting pills,
getting a gun, giving valuables away or writing a suicide note)?
If yes, describe:
Lifetime
Yes     No
□ □
Total # of
Attempts
______
Yes     No
□ □
Yes
No
□ □
Total # of
interrupted
______
Yes
No
□ □
Total # of
aborted or
self-
interrupted
______
Yes
No
□ □
Total # of
preparatory
acts
______
Past 3
months
Yes     No
□ □
Total # of
Attempts
______
Yes     No
□ □
Yes
No
□ □
Total # of
interrupted
______
Yes
No
□ □
Total # of
aborted or
self-
interrupted
______
Yes
No
□ □
Total # of
preparatory
acts
______
Most Recent
Attempt
Date:
Actual Lethality/Medical Damage:
0. No physical damage or very minor physical damage (e.g., surface scratches).
1. Minor physical damage (e.g., lethargic speech; first-degree burns; mild bleeding; sprains).
2. Moderate physical damage; medical attention needed (e.g., conscious but sleepy, somewhat responsive; second-degree
burns; bleeding of major vessel).
3. Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g., comatose with reflexes
______
intact; third-degree burns less than 20% of body; extensive blood loss but can recover; major fractures).
4. Severe physical damage; medical hospitalization with intensive care required (e.g., comatose without reflexes; third-degree
burns over 20% of body; extensive blood loss with unstable vital signs; major damage to a vital area).
5. Death
Most Lethal
Attempt
Date:
Enter Code
______
Initial/First
Attempt
Date:
Enter Code
______
Potential Lethality: Only Answer if Actual Lethality=0
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical damage, had
potential for very serious lethality: put gun in mouth and pulled the trigger but gun fails to fire so no medical damage; laying
on train tracks with oncoming train but pulled away before run over).
0 = Behavior not likely to result in injury
1 = Behavior likely to result in injury but not likely to cause death
2 = Behavior likely to result in death despite available medical care
Enter Code
______
Enter Code
______
Enter Code
______
© 2008 Research Foundation for Mental Hygiene, Inc.
C-SSRS—Lifetime Recent (Version 1/14/09)
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COLUMBIA-SUICIDE SEVERITY
RATING SCALE
(C-SSRS)
Since Last Visit
Version 1/14/09
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; Zelazny, J.;
Burke, A.; Oquendo, M.; Mann, J.
Disclaimer:
This scale is intended to be used by individuals who have received training in its administration. The questions contained
in the Columbia-Suicide Severity Rating Scale are suggested probes. Ultimately, the determination of the presence of
suicidal ideation or behavior depends on the judgment of the individual administering the scale.
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia Suicide History
Form, developed by John Mann, MD and Maria Oquendo, MD, Conte Center for the Neuroscience of Mental Disorders
(CCNMD), New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032. (Oquendo M. A.,
Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of research instruments. In M.B. First
[Ed.] Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.)
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 1051 Riverside Drive, New
York, New York, 10032; inquiries and training requirements contact posnerk@childpsych.columbia.edu
© 2008 The Research Foundation for Mental Hygiene, Inc.
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SUICIDAL IDEATION
Ask questions 1 and 2. If both are negative, proceed to “Suicidal Behavior” section. If the answer to question 2 is “yes”,
ask questions 3, 4 and 5. If the answer to question 1 and/or 2 is “yes”, complete “Intensity of Ideation” section below.
Since Last
Visit
1. Wish to be Dead
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up.
Have you wished you were dead or wished you could go to sleep and not wake up?
If yes, describe:
2. Non-Specific Active Suicidal Thoughts
General, non-specific thoughts of wanting to end one’s life/commit suicide (e.g., “I’ve thought about killing myself”) without thoughts of ways to kill
oneself/associated methods, intent, or plan during the assessment period.
Have you actually had any thoughts of killing yourself?
If yes, describe:
3. Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is different than a specific plan with time,
place or method details worked out (e.g., thought of method to kill self but not a specific plan). Includes person who would say, “I thought about taking an
overdose but I never made a specific plan as to when, where or how I would actually do it…and I would never go through with it.”
Have you been thinking about how you might do this?
If yes, describe:
4. Active Suicidal Ideation with Some Intent to Act, without Specific Plan
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as opposed to “I have the thoughts but I
definitely will not do anything about them.”
Have you had these thoughts and had some intention of acting on them?
If yes, describe:
5. Active Suicidal Ideation with Specific Plan and Intent
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it out.
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan?
If yes, describe:
Yes       No
□     □
Yes      No
□     □
Yes      No
□     □
Yes       No
□     □
Yes      No
□     □
INTENSITY OF IDEATION
The following features should be rated with respect to the most severe type of ideation (i.e., 1-5 from above, with 1 being the least severe
and 5 being the most severe).
Most
Most Severe Ideation:
_____
_________________________________________________
Severe
Type # (1-5)
Description of Ideation
Frequency
How many times have you had these thoughts?
____
(1) Less than once a week     (2) Once a week (3) 2-5 times in week (4) Daily or almost daily (5) Many times each day
Duration
When you have the thoughts, how long do they last?
(1) Fleeting - few seconds or minutes
(2) Less than 1 hour/some of the time
(3) 1-4 hours/a lot of time
(4) 4-8 hours/most of day
____
(5) More than 8 hours/persistent or continuous
Controllability
Could/can you stop thinking about killing yourself or wanting to die if you want to?
(1) Easily able to control thoughts
(4) Can control thoughts with a lot of difficulty
(2) Can control thoughts with little difficulty
(5) Unable to control thoughts
(3) Can control thoughts with some difficulty
(0) Does not attempt to control thoughts
Deterrents
Are there things - anyone or anything (e.g., family, religion, pain of death) - that stopped you from wanting to die or acting on
thoughts of committing suicide?
(1) Deterrents definitely stopped you from attempting suicide
(4) Deterrents most likely did not stop you
(2) Deterrents probably stopped you
(5) Deterrents definitely did not stop you
(3) Uncertain that deterrents stopped you
(0) Does not apply
Reasons for Ideation
What sort of reasons did you have for thinking about wanting to die or killing yourself? Was it to end the pain or stop the way
you were feeling (in other words you couldn’t go on living with this pain or how you were feeling) or was it to get attention,
revenge or a reaction from others? Or both?
(1) Completely to get attention, revenge or a reaction from others
(4) Mostly to end or stop the pain (you couldn’t go on
(2) Mostly to get attention, revenge or a reaction from others                     living with the pain or how you were feeling)
(3) Equally to get attention, revenge or a reaction from others
(5) Completely to end or stop the pain (you couldn’t go on
and to end/stop the pain                                                                         living with the pain or how you were feeling)
(0) Does not apply
08-Apr-2024
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____
____
Version 1/14/09
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SUICIDAL BEHAVIOR
(Check all that apply, so long as these are separate events; must ask about all types)
Actual Attempt:
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought of as method to kill oneself. Intent
does not have to be 100%. If there is any intent/desire to die associated with the act, then it can be considered an actual suicide attempt. There does not
have to be any injury or harm, just the potential for injury or harm. If person pulls trigger while gun is in mouth but gun is broken so no injury results,
this is considered an attempt.
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or circumstances. For example, a highly
lethal act that is clearly not an accident so no other intent but suicide can be inferred (e.g., gunshot to head, jumping from window of a high floor/story).
Also, if someone denies intent to die, but they thought that what they did could be lethal, intent may be inferred.
Have you made a suicide attempt?
Have you done anything to harm yourself?
Have you done anything dangerous where you could have died?
What did you do?
Did you______ as a way to end your life?
Did you want to die (even a little) when you_____?
Were you trying to end your life when you _____?
Or did you think it was possible you could have died from_____?
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, feel better, get
sympathy, or get something else to happen)? (Self-Injurious Behavior without suicidal intent)
If yes, describe:
Has subject engaged in Non-Suicidal Self-Injurious Behavior?
Interrupted Attempt:
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not for that, actual attempt would have
occurred).
Overdose: Person has pills in hand but is stopped from ingesting. Once they ingest any pills, this becomes an attempt rather than an interrupted attempt.
Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow prevented from pulling trigger. Once they pull the trigger,
even if the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and taken down from ledge. Hanging: Person has noose around
neck but has not yet started to hang - is stopped from doing so.
Has there been a time when you started to do something to end your life but someone or something stopped you before you
actually did anything?
If yes, describe:
Aborted Attempt:
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have engaged in any self-destructive behavior.
Examples are similar to interrupted attempts, except that the individual stops him/herself, instead of being stopped by something else.
Has there been a time when you started to do something to try to end your life but you stopped yourself before you
actually did anything?
If yes, describe:
Since Last
Visit
Yes
No
□ □
Total # of
Attempts
______
Yes      No
□ □
Yes
No
□ □
Total # of
interrupted
______
Yes
No
□ □
Total # of
aborted
______
Preparatory Acts or Behavior:
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or thought, such as assembling a
specific method (e.g., buying pills, purchasing a gun) or preparing for one’s death by suicide (e.g., giving things away, writing a suicide note).
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such as collecting pills, getting a gun,
giving valuables away or writing a suicide note)?
If yes, describe:
Yes
No
□ □
Suicidal Behavior:
Suicidal behavior was present during the assessment period?
Completed Suicide:
Answer for Actual Attempts Only
Actual Lethality/Medical Damage:
0. No physical damage or very minor physical damage (e.g., surface scratches).
1. Minor physical damage (e.g., lethargic speech; first-degree burns; mild bleeding; sprains).
2. Moderate physical damage; medical attention needed (e.g., conscious but sleepy, somewhat responsive; second-degree burns; bleeding of major vessel).
3. Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g., comatose with reflexes intact; third-degree burns
less than 20% of body; extensive blood loss but can recover; major fractures).
4. Severe physical damage; medical hospitalization with intensive care required (e.g., comatose without reflexes; third-degree burns over 20% of body;
extensive blood loss with unstable vital signs; major damage to a vital area).
5. Death
Potential Lethality: Only Answer if Actual Lethality=0
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical damage, had potential for very serious
lethality: put gun in mouth and pulled the trigger but gun fails to fire so no medical damage; laying on train tracks with oncoming train but pulled away
before run over).
0 = Behavior not likely to result in injury
1 = Behavior likely to result in injury but not likely to cause death
2 = Behavior likely to result in death despite available medical care
Yes       No
□ □
Yes     No
□ □
Most Lethal
Attempt
Date:
Enter Code
______
Enter Code
______
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