Neuroprotective vs. Neurostimulating Management Options for Amytrophic Lateral Sclerosis. A Multiple Trial Based Comparison

Doctoral Thesis / Dissertation, 2017

59 Pages, Grade: PG MEDICAL DOCTOR & CEO

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1.1 Dissertation Methodology
1.2 Aims and Objectives
1.3 Introduction

2.1 Literature Review on Controlled Trial of Riluzole in Amyotrophic Lateral Sclerosis
Material and Methods
Randomization and Criteria
2.2 Literature Review on Clinical trial with ceftriaxone in amyotrophic lateral sclerosis
Material and Methods Randomization and Criteria Figures
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2.3 Literature Review on Randomised, Double-Blind, Placebo-Controlled, Study of Safety and Efficacy of Dexpramipexole in Subjects with ALS
Material and Methods
Randomization and Criteria
2.4 Literature Review on Efficacy and Safety of MCI-186 Edaravone
Material and Methods
Randomization and Criteria

3.1 Literature Review on CY4031-VITALITY-ALS (TIRASEMTIV)
Material and Methods
Randomization and Criteria
3.2 Literature Review on Multi-Centre, Randomised Controlled Study of NeuRx ® Diaphragm Pacing System™ In Participants with A LS
Material and Methods
Page 6 of
Randomization and Criteria
3.3 Literature Review on Repetitive Transcranial Magnetic Stimulation (rTMS) in ALS
Material and Methods
Randomization and Criteria

(In chronological order with respect to literature review’s sequence)

5.1 Conclusions
5.2 Future Scope



Abbildung in dieser Leseprobe nicht enthalten


ALS, an incurable fatal syndrome (than being just a misnomer of disease), affecting each organ system and life (quality and quantity), through glutamate induced free radical and electrical injuries to nerves. This giant needs to be further dig into, with deeper investigations for newer management options and betterment of previous treatments, aiming a comparison of various strategies, to invent most sustainable and suitable choice for PALS. Broadly ALS can be classified as sporadic and familial, based on aetiology. There are various subtypes in each of them with regards to the genetic, pathological and nucleic acid mutational conflicts.

Like in a case of “Diabetes Mellitus”, we don’t haphazardly enlist all drugs and precautions, instead first classify them into pharmaco-therapeutic or lifestyle changes, similarly for ALS, I’ve proposed for a new management classification system for clinical purposes after feeling a need of such, near the end of dissertation.

Only approved and unavoidable option in present scenario is glutamic acid release inhibitor “Riluzole” and the basic or standard life care for the disease.

Broad spectrum antibiotic “Ceftriaxone” has been found to cross the blood brain barrier and increase GLT-1 channel, leading to fall in glutamate levels of nervous system and hence can be an add-on option to benefit more.

RPPX: Dexpramipexole; recently developed drug especially for SOD-1 and TDP-43 mutation ALS, showed mitochondrial protection and reciprocated it as improved ALSFRS. Though the medication can be a future option, but for now trials have failed to reflect major benefit on a 12 month follow up.

MCI186: Edaravone, by virtue of being antioxidant in character (supposedly); has gained FDA approval in 2017 due to promising results. Drug has been in use in USA since May 2017 and will be introduced in European market following political, copyright and legal decisions in time.

Tirasemtiv activates muscle troponin complex leading to increased sensitivity of neuromuscular junction (NMJ) for calcium (Ca2+) and hence help to overcome the fatigue of ALS. Study is yet undergoing with biggest hope amongst all newer options.

DPS using local electrodes in diaphragm, overcome respiratory efforts in ALS affected patients. Being an “HDE” due to dramatic symptomatic relief, it’s being considered in guidelines, even after multiple failed trial results on 12 month follow up and absolutely no effect on survival and disease progression.

Motor cortex stimulation via “rTMS” does look efficacious in improving nerve conduction delay/lag of ALS, but the positive differences in its favour are null with respect to placebo/sham electrodes. There might be an option with further digging in its use, methodology and ergonomic developments.

Few spotlight advancements yet under development, but worth at least mentioning; are also put up into the ending chapters. They do deserve a keen outlook alongside rest of the study details with respect to futuristic vision. Overall juice of upcoming discussion, which is the ultimate answer to our primary query of perfect management for ALS would be an emptiness, because none of developments till date have proven to be efficient enough, demanding a combined approach of NPMs and NSMs, in proportions as required, per case.



Dissertation Methodology

The puzzles of ALS, to understand them inclusive of management options, I’ve done a strenuous study with a totally unexplored and different perspective; which as far as I’ve come to know, hasn’t been given thought yet, and hence a proposal of introducing new management binary classification system. The perspective of ALS, I’ve put up here; have embodied its essence into a query, leading to evolution of this dissertation. In an attempt to answer main question, “Neuroprotective versus Neurostimulating approach as solitaire or combination for PALS”, this thesis is organized into abstract and five chapters, targeting to answer the aforementioned.

Chapter 1 is general introduction, a literature review on the disease, i.e. ALS including general current management outlines.

Chapter 2 is the evaluation of four drugs, which are either “in practice”, “approved” or “promising” Neuroprotective medications. I studied and analysed their trial results and presented them here. The medications are, Riluzole, Ceftriaxone, Dexpramipexole and Edaravone.

Chapter 3 is about one drug and two therapies namely; Tirasemtiv, Diaphragmatic Stimulation and Trans cranial Magnetic Stimulation. First two are extremely expectant with respect to ALS that later one is even in practice on humanitarian grounds irrespective of reports and trial outcomes.

Chapter 4 is the cream of all aforementioned trials and researches, and represents ‘Critical analysis’ section in this dissertation.

Chapter 5 embraces summary, future scope into this “untreatable” disease and a proposal of adding “TOS-ALS” therapy classification system.

Chapter 6 enlists the references used.

All the aforementioned chapters on medications and therapies, i.e. chapter 2 and 3, are sub organised into following categories;

A. Introduction
B. Material and Method
C. Randomization and Criteria
D. Figures
E. Results

An important aspect of this work is the list of abbreviations, which would be quintessential while reading and understanding the information acquired by various studies about to be discussed, including general aspects of disease itself.

Aims and Objectives

- Primary Aim:

Evaluate major therapeutic options for ALS in a comparative manner of with and without combinations in between them.

- Statement Of Problem and Objective:

ALS, a fatal disease of 03 years average survival, needs further efforts for hunting down its cure, symptomatic relief, longevity and QOL. Such issue has lead us to evaluate the flip sides of “coin of management”, under personally developed therapeutic classification of “Neuroprotective Methods (Abr: NPMs)” vs. “Neurostimulating Methods (Abr: NSMs)”.

- Proposal:

Introduction of new therapeutic classification system under the umbrella of ALS, “TOS-ALS”, i.e. “Therapy Options Classification system for ALS” pointing out binary tracts of; Neuroprotective and Neurostimulating methods, and hence avoiding bizarre enlisting of all drugs, therapeutic procedures and their combinations.


- Amyotrophic lateral sclerosis (ALS), or Motor Neuron Disease (MND), is most common degenerative disease of motor neurons. Till date it’s incurable and fatal.
- “Amyotrophic” reflects to the atrophy of denervated muscle fibres.
- “Lateral sclerosis” refers to changes in the lateral columns of the spinal cord, UMN and/or LMN axons degenerate and replaced by fibrous astrocytes (gliosis).
- ALS was first mentioned in 1869 by neurology physician from France, Dr Jean-Martin Charcot and that’s the reason for it to be called Charcot disease.
- In United States, baseball legend Lou Gehrig was diagnosed with the disease in 1939, so also known as Lou Gehrig's disease.
- Professor Stephen Hawking, author of “A Brief History of Time” and physicists of current era, is an exceptional case. He has survived with ALS for over 40 years and still counting.

Types of ALS

- Classic Sporadic ALS (>70%);

It’s the most common type of ALS. It begins usually as weakness in one part of body and spreads gradually to the rest. Ventilatory failure reflects as death in 3 years on average, since the onset of focal weakness. Disease progression ranges a few months to 10 years. Affects motor neurons at various levels supplying multiple regions: o LMNs residing in anterior horn of the spinal cord and brain stem; leading to progressive muscle weakness, wasting (atrophy) and fasciculation, with loss of reflexes and muscle tone. o Corticospinal UMNs that reside in the precentral gyrus, involved in planning or orchestrating the work of the upper and lower motor neurons leading to milder weakness associated with spasticity and abnormal brisk reflexes. o Corticospinal UMNs of prefrontal motor neurons leading to special forms of cognitive impairment including, executive dysfunction, an altered awareness of social implications of one’s circumstances and, maladaptive social behaviours. o Aspiration pneumonia and medical complications of immobility contribute to morbidity.

- Progressive muscular atrophy and flail limb syndrome;

Disease restricted to LMNs. When the involvement is asymmetrical, disorder is termed progressive muscular atrophy (PMA), while with symmetrical it’s flail limb syndrome. PMA progresses at the same rate as classic ALS.

- Primary lateral sclerosis (PLS);

Only UMNs are involved. Course is measured in decades. It progresses slower than classic ALS.

- Progressive bulbar palsy- PBP (<20%);

Rarely ALS is restricted to bulbar muscles. In most cases evolves to classic. PBP progresses slower than classic ALS.

- Familial ALS (5%);

A family history of ALS is seen. Mostly autosomal dominant with reduced and variable penetrance, but other patterns like X-linked or autosomal recessive are also seen.

Signs & Symptoms

- In 75-80% PALS, begins with limb involvement (classic).
- Initial complaints:-

- Lower limb onset: tripping, stumbling, foot drop, "slapping" gait.
- Upper limb onset: decreased finger dexterity, cramps, and stiffness with weak and wasted intrinsic hand muscles with or without wrist drop. o Bulbar onset (<20%), initial complaints are: slurred speech, hoarse and decreased speech volume, aspiration during feedings.

- Progression of bulbar onset ALS leads to:

- Voice hyper nasality, strained quality, loss of speech. o Swallowing difficulty starting with liquids first. o Drooling.

- Emotional and cognitive difficulties in PALS are: o Involuntary laughs or cry.
- Depression.
- Impaired executive function.
- Maladaptive social behaviour.

- Features of advanced disease are: o Severe muscular atrophy.
- Spasticity compromised gait and manual dexterity.
- Frequent muscle cramps.
- Painful joint contracture of immobility.
- 15% PALS meet criteria for FTD.

Course of disease

- Loss of motor neurons reflects pathophysiology and clinical expressions with characteristic spinal cord cross sections. At the level of muscles, loss of innervation of individual units.
- In early disease, surviving nerves establish connections and re-innervate motor units that have lost connection to axonal death; hence larger motor units are formed. These large units manifest in histologic stains as fibre-type grouping and with specific EMG results. Later when motor neurons units die, atrophy ensues.
- Till re-innervation can keep up, clinical weakness won’t be detectable, although loss of dexterity may occur. As motor units grow larger and their count decreases, affected muscle fatigues faster; consequently one of the first symptoms is fatigability. As the number of motor units innervating a muscle decreases further, re-innervation can no longer complement, leading to permanent weakness and progressing gradually to atrophy.

Disease progression

- Effective survival predictor is ALSFRS-R, a 12-item self-reported questionnaire producing score between 48 (normal) and 0 (severe disability).
- Progression estimates derived as a ratio, numerator is functional loss obtained using ALSFRS-R, FVC% of predicted, MUNEs and the denominator is time from onset to evaluation.
- Roche et al have proposed “system of stages”, the timing of which is standardized as proportion of elapsed time through the course of ALS.
- Stage 1: Symptom onset (first region)
- Stage 2A: Diagnosis (35% through the disease course)
- Stage 2B: Involvement of second region (38%)
- Stage 3: Involvement of third region (61%)
- Stage 4A: Need for gastrostomy (77%)
- Stage 4B: Need for NIV (80%)


- Despite intense research, no single direct mechanism for ALS has been identified, but all ultimately leads to raised glutamate levels in nervous system.
- Following proposed mechanisms seen with variable penetration:

- Excito-toxicity: - key mechanism secondary to over activation of glutamate receptors. o Oxidative stress of free radical formation: - A cause since discovery of mutations in gene coding free radical scavenging enzyme SOD 1. o Mitochondrial damage: - An adjuvant mechanism. o Autoimmunity to calcium channels: - Lead to decreased MTC sensitivity. o Cytoskeletal proteins in cellular inclusions: - Implicating defective proteasome system leading to neurofilament defects. o Defective RNA: - Aggregation of proteins involved in RNA metabolism has been seen in most forms of ALS.
- Prion like propagation of miss folding of proteins in SOD1 and TDP-43 has been a mechanism for the regional spread of symptoms. o Apoptosis is the ultimate method of neuronal death, associated with fibrosis and gliosis.

- Axonal degeneration

- Motor axons die by Wallerian degeneration and large motor neurons are affected more than smaller ones, due to death of anterior horn cell body.
- As the axon breaks down, surrounding Schwann cells catabolize myelin sheath and engulf the axon, breaking it into fragments, forming ovoid compartments of axonal and myelin debris, termed myelin ovoid. Ovoids then are eaten by macrophages.

- In long term, primary motor and premotor cortex atrophy is also seen.
- Degeneration also occurs peripherally and collaterals of surviving axons can be seen attempting to reinnervate.
- On muscle biopsy, various stages of atrophy are noted from aforementioned pattern.
- In typical ALS, certain motor neurons are spared until very late:

- In brain stem- Oculomotor, Trochlear, and Abducens nerves.
- In spinal cord- Posterior columns, spinocerebellar tracts, nucleus of onuf (in laminae IX of anterior horn of sacral region controlling bowel and bladder), and Clarke column (posterior dorsal thoracic nucleus, interneurons in Lamina VII intermediate zone, located from T1 to L3-L4 level, important for proprioception).

- Though Clarke column can be affected early in familial ALS.
- Pathways to cell death in ALS; may be mediated by following:

- Oxidative damage
- Mitochondrial dysfunction
- Caspase mediated (apoptosis)
- Defects in axonal transport
- Abnormal growth factor expression
- Glial cell pathology
- Glutamate excitotoxicity
- Abnormal proteins aggregation

- Derangements of RNA metabolism is the core pathophysiology:-

- SOD1 or ALS1 gene: 10-20% familial ALS results from SOD1 gene mutation, also known as ALS1, associated with LMN disease. In familial ALS from this alanine-to-valine mutation in codon 4, average survival is 12 months.
- TARDBP gene: TDP-43 is a nuclear RNA-processing protein. TDP-43-positive cytoplasmic inclusions identified in sporadic ALS and FTD. Chromosome 1 mutation for TDP-43 was found in sporadic and some familial patients.
- FUS/TLS gene: Located on chromosome 16. Some patients have cytoplasmic inclusions containing FUS/TLS but not TDP-43. Mutations in FUS account for 4% of familial ALS.
- C9orf72 mutation: A large hex nucleotide (GGGGCC) repeat expansion in first intron of C9orf72; function of which is unknown, accounted for chromosome 9p21-associated ALS, FTD and 50% of familial ALS. It’s most common mutation in sporadic ALS and FTD in Finnish population and, 33%+ familial ALS of European ancestry.
- NIMA related kinase 1/ NEK1 gene: Highly expressed in germ cells, involved in meiosis and respond to DNA damage from radiation. Gene defects lead to polycystic kidney disease and ALS. Discovered by Project MinE-ALS Association through ALS Ice Bucket Challenge, AUG 2014- JULY 2015 using raised 115M USD.

Risk and Triggering Factor

- Smoking: Incidence based risk factor for sporadic ALS by induction of nucleic acid changes, supported by clinical association.
- Age: Age-specific incidence of sporadic ALS suggested increased risk of mutations and accumulations in nucleic acids leading to ALS. Incidence increases with age in a logarithmic fashion, and the slope of log incidence vs. log age is 5, suggesting a multi-step process, analogous to carcinogenesis, with 6 steps needed for ALS to be triggered.
- Cell-to-Cell transmission: Mis-folded protein transmission within motor network. The difference from prion disease is lack of transmissibility by inoculation to other organisms and confinement to a neuronal system with a common function.
- Military service: Services in World War II, Korean War, Vietnam, Persian Gulf War; exposure to pesticides, unethical hormone use, excessive smoking and physical exercise; all associated with ALS.
- Western Pacific Guamanian ALS/PDC: Ingestion of Cycas Micronesica predisposes to ALS; its toxic alkylating components induced changes exacerbating age-dependent nucleic acid mutations. Complications
- Progressive inability in daily activities and ambulation.
- Aspiration pneumonia
- Respiratory insufficiency
- Wheelchair-bound or bedridden leading to decubitus ulcers and infections
- DVT and PE.


- International occurrence: Age-adjusted European incidence data are similar to those for members of the US population of European descent. MND kills five people every day in UK.

Finland has the highest rate of ALS in the world; the disease occurs nearly twice as frequently as it does in other European ancestry. Discovery of mutation in C9orf7 gene have confirmed it to be due to genetic factors.

Race: ALS affects whites more often than non-whites; white-to-nonwhite ratio of 1.6:1.

- Sex and Age: Initially incidence is higher in men, with an overall male-to-female ratio of 1.5-2:1, but in 40s or 50s, it tends to equalise. Mean age of onset for sporadic is 65 years while familial ALS ranges from 46-55 years.

Differential Diagnosis

- Patients with a new focal presentation:
- UMN bulbar signs: Brainstem lesions including syrinx, stroke, and demyelinating forms of other degenerative diseases o LMN bulbar signs: Cranial nerve palsies o UMN limb signs: Cervical myelopathy, cord tumour, hereditary spastic Para paresis, transverse myelopathy, HIV-related myelopathy, syrinx o LMN limb signs: Radiculopathy, plexopathy, neuropathy
- For patients with more advanced disease:
- UMN signs - Compressive myelopathy, syrinx
- LMN signs - CIDP, multifocal motor, toxic, or metabolic neuropathies or myopathies such as inclusion body myositis or polymyositis.

- Rapid onset (over hours, days or a few weeks):

- Myasthenia gravis
- Guillain-Barre syndrome
- Acute motor axonal neuropathy
- Virus- West Nile, Coxsackie, Herpes Zoster, Polio, Botulism.

- Other problems to consider:

- Tay-Sachs/GM 2 gangliosidosis disease (late onset)
- Mercury or lead poisoning / Copper deficiency myelopathy
- Motor neuropathies/Spinal cord arteriovenous malformation
- Monoclonal gammopathies / Paraneoplastic neuropathy/ LEMS/ MS


- The diagnosis of ALS is primarily clinical.
- Definitive diagnosis may not be possible in early ALS. Confirmation required by documenting progressive nature and exclude alternative diagnosis. Electro diagnostic testing ads up to the accuracy.
- WFN has developed a diagnostic algorithm combining clinical and electrophysiological findings;

- Clinically definite ALS: UMN + LMN signs in at least 3 body segments
- Clinically probable ALS:

UMN + LMN signs in at least 2 body segments and some

UMN signs above LMN signs in one segment. o Clinically probable, laboratory-supported ALS:

UMN + LMN signs in 1 segment or,

UMN signs in one region with EMG of LMN signs in at least 2 limbs o Clinically possible ALS: UMN + LMN signs in one segment, plus;

UMN signs alone in at least 2 segments, or

LMN signs in segments above UMN signs o Clinically suspected ALS: Pure LMN syndrome with other causes excluded.

- Electro diagnostic hallmark: Normal sensory nerve conduction and abnormal motor nerve conduction with reduced motor action potential.


- It’s a fatal disease with median survival of 3 years from clinical onset. About 20% live 5 years after diagnosis, and less than 5% survive for roughly 10 years.
- Long-term survival is associated with younger age of onset, male and limb onset.
- ALS associated with FTD has shorter survival than classic.


- Currently mainstay of ALS therapy is adaptive management directed at clinical manifestations.
- Summarised management options:

- Riluzole offered to all patients to slow disease progression. The glutamate pathway antagonist Riluzole is the only medication approved for ALS till now. o If there’s impaired oral intake; PEG can be placed to recover normal body weight. PEG can only be placed when FVC% is above 50% predicted due to lowest risk of insertional side effects.
- NIV should be offered to treat respiratory insufficiency, prolong survival and slow FVC decline; considered at the earliest sign of nocturnal hypoventilation.
- Mechanical suction required to clear secretions in patients of low peak cough flow during ALRTI.
- Invasive ventilatory support with tracheostomy is considered in respiratory failure with largely neurologically intact patients in whom secretions cannot be managed and hence won’t benefit from NIV.
- Muscle relaxants for spasticity.
- Combination of dextromethorphan and quinidine for emotional instability of pseudo bulbar effects.
- Anticholinergic and sympathomimetic for sialorrhea, mucolytic for thickened secretions. o Lorazepam for anxiety. SSRIs for depression. NSAIDs, tramadol,, morphine or transdermal fentanyl for pain.

CHAPTER 2: Major Neuroprotective Methods

2.1. Literature Review on Controlled Trial of Riluzole in Amyotrophic Lateral Sclerosis 2,3


- Glutamate, which do form in CNS as being a variant of transport form of glutamine or stimulant glutaminergic electrical tract.
- These highly charged chemical bodies lead to early and accelerated nerve cell apoptosis via accumulation through calcium dependent gated paths.
- Hence any formulation capable of interfering the above system can be of some use in terms of ALS therapy or relief or any intervention.
- This made Riluzole, ie 2-amino-6-(trifluoromethoxy) benzothiazole or, RP 54274; eligible to get checked by a clinical trial under GMP European guidance, in a progressive, bias free, randomised and placebo controlled manner. The attempt hence done years back is known as “controlled trial of Riluzole in ALS”.
- The RP 54274 has already shown the ability of leak proofing the glutamic acid release in proximal nervous convex synapses, and hamper the distal, synaptic post ‘fluid-zone-vesicular’ propagation of excitatory amino acid (EAA). Material and Methods
- A prospective, randomized, double-blind, placebo-controlled, stratified trial to determine whether Riluzole is beneficial to PALS was conducted according to the European guidelines for good clinical practice.
- Study Details

- Age: 20 to 75 years.
- Clinical status: Probable or Definite ALS at entry. (El Escorial-Revised)4,5
- Inclusion
- Informed consent (spouse assistance if required)
- Approval of protocols by Pitie-Salpetriere Hospital Ethics committee (Paris).

- Exclusion:

- Any sign of conduction blocks of motor nerves, sensory nerves, or both on electromyography, paraproteinemia on immunoelectrophoresis, substantial lesions accounting for clinical signs on CT/MRI, or signs of dementia.
- More than five years since onset
- Any life-threatening diseases
- FVC of 60% or less of expected
- Undergone tracheostomy, any hepatic or renal dysfunction or Pregnant.

Randomization and Criteria

- Randomization
- Stratified according to the centre where the patient was treated (one of seven centres) and the site of onset of disease (limb or bulbar).
- Patients with bulbar-onset disease were defined as having initial signs and symptoms in the bulbar region, but they had clinically definite or probable ALS at enrolment, similarly limb-onset disease had first symptoms in limbs, even if they had bulbar involvement at the time of enrolment.
- Treatment assignments were made separately in each centre based on randomization codes established by blocking. Patients were given either 100 mg of Riluzole per day in 50-mg tablets or placebo, to be taken orally twice a day, before meals.
- The tablets were provided by Rhone-Poulenc Rorer (France).

- Outcome Measures and Follow-up
- Each patient had scheduled follow up every two months hence all the scores were evaluated at entry and every two months thereafter. Investigators were trained to improve evaluations.

- Primary Efficacy Outcomes:-

- Survival and changes in functional status after 12 months of treatment.
- Events included in survival rate were death from any cause and tracheostomy, since the terminal ALS associated respiratory failure leads to either event(s).
- Functional status assessed with a four-point rating scores of limb function, bulbar function, clinical examination and symptoms reported. Limb and bulbar function were evaluated with modified Norris scales6 (maximal score for limb function-63; for bulbar function-39).

- Secondary Efficacy Outcomes:-

- Muscle-testing scores, respiratory function, scores on the Clinical Global Impression of Change scale, and patient's subjective evaluation of fasciculation, cramps, stiffness, and tiredness, expressed on four 100-mm visual-analogue scale at entry and every 2 months thereafter.
- 22 muscle functions assessed with patient in sitting position as per five-grade scale of The Medical Research Council Paris (maximal score, 110).
- Respiratory function assessed with FVC% of expected at entry and every 6 months thereafter.
- Safety, intercurrent events, withdrawal from treatment, and loss to follow-up
- Adverse effects of medication and intercurrent events were noted at each visit by direct questioning, clinical examination and laboratory findings. All determinations of laboratory values were performed in the same laboratory (CERBA, Saint Ouen l'Aumone, France).
- Hepatic function and muscle enzymes monitored every two weeks from entry to month 7 and afterwards every two months.
- Biochemical and hematologic evaluations were performed at entry and every two months thereafter.
- Determination of study drug plasma concentrations by taking blood samples (10 ml in heparinised tubes), monthly from month 1 to month 4, and every two months thereafter. Samples were drawn before morning dose and sent to central laboratory. After centrifugation at 1300g for 10 minutes, the plasma was frozen at -18 °C until it was processed at the end of study.
- Withdrawal from treatment due to; adverse events, increased ALT to more than thrice the normal range, and the withdrawal of consent. Withdrawal from treatment was not a reason for termination of the study, and follow-up of patients every two months continued in an intention-to-treat analysis.
- In follow-up loss, administrator sought patient’s detail from kin(s) or family physician or requested death certificate from city council, as per patient's scenario.
- Sample Size and Power

- Exploring previous studies7,8,9,10 and data11 ; the 12-month survival rates were 35% for bulbar-onset and 65% for limb-onset disease.
- Overall estimated survival rate of 55% in placebo group, given the expected ratio of one patient with bulbar-onset to every two patients with limb-onset ALS.
- 110 PALS as sample prospectively fixed for an improvement of 55% to 85% in 1 year survival rate detection, with an alpha level of 5% and a beta level of 90%, by one-tailed test.


- Demographic Data

- 155 PALS enrolled (32-bulbar onset and 123- limb onset). Date of data censor (November 30, 1991) was set 12 months after enrolment of final patient. After this date, trial continued in double blind conditions until efficacy analysis in March 1992, after which PALS on placebo were switched to Riluzole.
- Limb and bulbar functional scores and muscle strength were presented for the 12 months of treatment. While in the analysis of survival, data are reported for first 12 month period and continued till end of placebo controlled period (March 12, 1992). The interval between randomization and March 12, 1992, ranged from 483 to 632 days (median 573). Analysis of safety was presented after placebo-controlled period.

- 77 patients randomly assigned to Riluzole (62 limb-onset and 15 bulbar-onset), and 78 patients to placebo (61 and 17 patients respectively).
- All the patients were probable or definite ALS as per El Escorial (R) criteria.
- The differences between bulbar and limb onset disease were as expected.
- Five patients had familial ASL (1 in placebo and 4 in Riluzole group).
- Survival

- None loss to follow-up in analysis of survival.
- There was a significant difference in survival between both groups.
- At 12 months, 45/78 patients in placebo group (58%) remained alive, as compared with 57 of 77 in Riluzole group (74%) (P = 0.014).
- By the end of the placebo-controlled period 29 of 78 patients in the placebo group (37%) remained alive, as compared with 38 of the 77 patients in Riluzole group (49%) (P = 0.046).
- Median survival was 449 and 532 days in placebo and Riluzole groups, respectively.
- In bulbar ALS, 6 of 17 patients in placebo group (35%) remained alive at 12 months, while 11 of 15 patients in Riluzole group (73%) (P = 0.014). By the end of placebo-controlled period, there was a significant difference between treatments: 3 of 17 patients in placebo group (18%), compared with 8 of 15 Riluzole group (53%) (P =0.013), stayed alive.
- In limb-onset disease, improved survival at 12 months in Riluzole group with 46 of 62 patients (74%) still alive, as compared with 39 of 61 in placebo group (64%), hence the results were not statistically significant (P = 0.17). By end of placebo-controlled period, 26 of 61 PALS in placebo group (43%) remained alive, while 30 of 62 patients in Riluzole (48%) (P = 0.355). There was no apparent gain in median survival.
- Stepwise analysis of risk factors (by Cox proportional hazards method) using; age, duration of disease, FVC%, bulbar function, tiredness and stiffness scores, as prognostic variables at entry. After adjustment for variables, difference in survival between treatments was significant only at 12 months (P = 0.005); and barely significant by placebo-controlled period (P=0.058).
- Overall, Riluzole therapy reduced mortality by 38.6% at 12 months and by 19.4% at 21 months (end of placebo-controlled period), an effect that is both clinically and statistically significant.
- Comparatively, treatment effect was greater in PALS of bulbar onset.

- Functional Evaluations

- On 12 months follow-up, 80% of all scheduled visits were completed. 5 patients were with only one evaluation (3 in placebo and 2 in Riluzole group) whose data could not contribute to functional scores, but there data retained for initial value estimation.
- For each functional score, deterioration was slower in Riluzole group than placebo. Only muscle testing score was striking with 33.4% reduction in rate of deterioration at 12 months. Treatment assignment, site of disease onset and effects showing the interaction between these two factors were included in model used for analysis.
- The effect of treatment assignment was noticeable, indicating that the effects of treatment were similar regardless of the site of disease onset.
- Adverse drug reactions reported worsening of asthenia and spasticity; increase in ALT or AST, or both; and mild to moderate raise in blood pressure.
- 19 patients (6 in placebo and 13 in Riluzole group) had increased aminotransferase(s) levels. These increases occurred 42 to 267 days after randomization in Riluzole group, and 23 to 503 days in placebo group.
- Increased ALT more than thrice normal limit was observed in 6 PALS of Riluzole group and 3 in placebo group. None had a value of more than five times.
- Among Riluzole group’s raised ALT, 5 were withdrawn, whereas 1 continued. In this one patient ALT remained within twice the normal value.
- Raised AST found in 11 patients of Riluzole and 3 in placebo group.
- 1 patient in the Riluzole group had an interruption of treatment, began treatment again, and remained in treatment until the end of study, with AST ranging up to four times of normal value; the ALT remained less than twice the normal.
- Concomitant increases in both aminotransferases occurred in 5 patients in Riluzole group but none in placebo group.
- PALS in Riluzole group who withdrew from treatment due to raised aminotransferases, the levels returned to base-line within two months after discontinuation.
- Overall 44 PALS discontinued during the study (27 on Riluzole and 17 on placebo). Among the 27 patients in Riluzole group, 19 discontinued treatment because of adverse experiences, as compared with 9/15 in placebo group.

2.2. Literature Review on Clinical trial with ceftriaxone in amyotrophic lateral


- Multi-centre clinical trial collaborated among The ALS Association, NINDS and several other organisations finding better treatment for ALS.
- Purpose: Evaluate safety and efficacy of ceftriaxone treatment in ALS.
- Study: Randomised double blinded.
- Primary Outcome Measures: Survival as per ALSFRS-R.
- Secondary Outcome Measures:

- FVC% predicted with QOL.
- Evaluation of multiple extremity muscles using HHD.
- Long-term safety and tolerability of ceftriaxone.
- Stage III Trial Start Date: May 2009, Stage III Trial completion date: November 2012

Material and Methods

- Detailed Description:

- Since increased glutamate is related to neural apoptosis, researchers want to study antibiotic that decreases its level near nerves.
- Ceftriaxone— semi-synthetic, third generation cephalosporin; may increase the level of a protein that decreases glutamate levels near nerves suggesting that it may protect motor neurons from injury. Drug is approved by US FDA for bacterial infections but not ALS. It has never been given for a long period like such as months or years.
- Ceftriaxone induced EAAT2 leading to glutamine formation from glutamate. EAAT2 or SLC1A2 also increases GLT-1 function with further glutamate clearing.
- Ceftriaxone also hinder Hippocampal CA1 buffering that stop glutamate clearance.
- Goals: Evaluate safety and effectiveness of ceftriaxone for ALS on long-term.
- PALS randomly assigned into ceftriaxone (2/3rd) or placebo (1/3rd) for 12 months.

- Eligibility:

- Age: PALS, at least 18 years of age
- Genders: Both
- Accepts Healthy Volunteers: No

- Study consist of three stages:

- First stage- whether ceftriaxone enters CSF in amounts enough of benefits.
- Second stage- Check safety and side effects of drug if taken daily for at least 20 weeks.
- Third stage- To determine if it prolongs survival and slows functional decline.

Randomization and Criteria

- Inclusion Criteria:

- PALS of 18 years and above.
- Participants must be able to undergo study procedures and have a caregiver who will be available to help with daily medication administration.
- Should live within a reasonable distance of the study site. o Exclusion Criteria:
- Into any other research for ALS, or a history of sensitivity to cephalosporin.

Figures and Results

- Primary Outcome Measures:

- Survival Time: From date of randomisation until date of death, tracheostomy or PAV, assessed at the time of drug discontinuation and every 2 months thereafter till study.
- Survival, as median day of survival.
- Changes in ALSFRS-R, based on 8 weekly measurements from baseline up to 1 year.

- Secondary Outcome Measures:

- Change in vital capacity percentage: Predicted based on age, gender, and height and is performed as SVC% every 12 weeks from baseline until 01 year.
- Change in evaluation of multiple extremity muscles:

- HHD is used to evaluate muscle strength.
- Six proximal muscle groups examined bilaterally in both upper and lower extremities (shoulder flexion, elbow flexion, elbow extension, hip flexion, knee flexion, and knee extension).
- In addition, wrist extension, first dorsal interosseous contraction and ankle dorsiflexion were measured bilaterally.
- HHD was performed using percentage change from baseline strength value for each muscle group, considered 100%.
- During successive visits, strength for each muscle group was measured and calculated as percentage of initial baseline value.
- Upper and lower extremity values were calculated as sum of all tests for that extremity to create one mega score for each extremity.
- Calculations were based on measurements every 12 week from baseline to 1 year. o Change in ALSQOL:
- Developed, tested and validated in PALS, and isn’t a health-related QOL scale.
- Consists of 59 questions about severity of symptoms, mood, intimacy and social issues.
- Each question is scored from 0-10.
- Total score ranges from 0-590, with 590 representing highest quality.
- Measurements done every 12 weeks from baseline to 1 year.

- Arms
- Active Comparator: Ceftriaxone
- 2/3rd PALS assigned to 4 gram BD in double blinded pattern.
- Administered IV central venous catheter. o Placebo Comparator: Placebo
- 1/3rd assigned to placebo.
- Paediatric multivitamin solution via central venous catheter, IV-BD.

- Description:

- Goal(s): Evaluate safety and effectiveness of ceftriaxone in ALS, as prolonged use.
- 600 PALS enrolled.
- PALS randomly assigned to get ceftriaxone or placebo for 12 months.
- Start (and completion) dosage data
- Ceftriaxone: 340 (162) o Placebo: 173 (77)
- Reason for non-completion
- Ceftriaxone: 168- died, 5- lost to follow up, 5- withdrew o Placebo: 86- died, 1- lost to follow up, 9- withdrawal
- Baseline Measures:
- Mean Age: - Ceftriaxone- 55.6; Placebo- 54.8 o Gender:-

- Female :- Ceftriaxone- 131; Placebo- 72
- Male:-Ceftriaxone- 209; Placebo- 101 o Ethnicity:-
- American or Alaska Native:- Ceftriaxone- 2; Placebo- 0
- Asian:- Ceftriaxone- 6; Placebo- 5
- Native Hawaiian or Pacific Islander:- Ceftriaxone- 1; Placebo- 0
- African American:- Ceftriaxone- 8; Placebo- 3
- Caucasian:- Ceftriaxone- 322; Placebo- 163 o Region of Enrolment: -
- United States:- Ceftriaxone- 293; Placebo- 151
- Canada :- Ceftriaxone- 47; Placebo- 22 o ALS Family History:-
- Positive:- Ceftriaxone-26; Placebo-8
- Negative:- Ceftriaxone- 307 ; Placebo- 161
- Unknown:- Ceftriaxone- 7; Placebo- 4 o Site of Onset:-
- Limb:- Ceftriaxone- 257; Placebo- 137
- Bulbar :- Ceftriaxone- 75; Placebo- 35
- Both:- Ceftriaxone- 8; Placebo- 1 o Concomitant Riluzole Use:-
- On Riluzole:- Ceftriaxone- 249; Placebo-128
- Not on Riluzole:- Ceftriaxone- 91 ; Placebo- 45
- Vital capacity mean (SD):- Ceftriaxone- 87.9% (16.6); Placebo- 91.1% (18.4)

2.3. Literature Review on Randomised, Double-Blind, Placebo-Controlled, Study of Safety and Efficacy of Dexpramipexole in Subjects with ALS25,26,27


- Study Start Date: March 2011; Completion Date: November 2012.
- Current trial criticise RPPX in 02 parallel screening systems:
- Well powered, sibling-matched, gender-balanced survival efficacy screening in high copy mutant SOD1.
- High-content neurone survival screening in rat cortical neurone transfected with wild or mutant TDP43.
- In cells transfected with mutant or wild TDP43, significant survival was seen at 10 u M RPPX.
- Systems also reflected both; non cellular autonomous and neuronal autonomous mechanisms, i.e. mutant as well as wild variant degeneration.

Material and Methods

- Aim- Determine whether dexpramipexole 150 mg BD is safe and effective for ALS.
- Drug: Dexpramipexole vs. Placebo
- Phase 3
- Study Type: Interventional
- Design:

- Allocation: Randomised
- Intervention: Parallel assignment
- Masking: Double blinded

- Background:

- In phase 2, dexpramipexole 25-150 mg BD was well tolerated for 9 months and had significant benefit towards high dose in function and mortality of PALS.
- Dexpramipexole (KNS-760704)50, enantiomer of Pramipexole has improved mitochondrial function conferring cellular protection in neurone under stress.

Randomisation and Criteria

- A randomised, double-blind, placebo-controlled phase 3 trial (EMPOWER), at 81 medical centres in 11 countries.
- Allocated PALS in 1:1 ratio for either dexpramipexole 150 mg BD, or matched placebo for 12-18 months.
- Stratified by trial location, site of onset and use of Riluzole in history.
- Primary endpoint:

- CAFS score: - As per; changes in ALSFRS-R or time death up to 12 months. o Assessed in PALS who had at least one dose and at least one post-dose ALSFRS-R measurement or died.
- Study details27 :-
- Primary Outcome Measure:

- Combined functional scores adjusted for mortality. [Time Frame: 12 months] o Secondary Outcome Measures:
- Time to death [Time Frame: 18 months]
- Time to Respiratory decline: lesser or equal to 50% predicted upright SVC%. [Time Frame: 18 months]
- Change in MSM, determined by HHD mega score [Time Frame: 12 months]
- Change in ALSAQ-5 total score [Time Frame: 12 months]
- Population pharmacokinetics. [Time Frame: 18 months]
- Incidence of adverse events. [Time Frame: 18 Months] o Arms and Assigned Interventions
- Experimental Drug: Tab. Dexpramipexole 150mg BD for 18 months.
- Comparator Drug: Placebo for 18 months, as above. o Eligibility
- Age:18 to 80 Years
- Sex: Both
- Healthy Volunteers: No

- Criteria
- Inclusion Criteria:

- Onset of first symptoms within 24 months prior to Day 1.
- WFN El Escorial criteria are met for a possible, laboratory-supported probable, probable, or definite ALS.
- Upright SVC of 65% or more at screening.
- If never taken Riluzole, consider eligible.
- If currently on Riluzole, then should be on fixed dose for 60 days minimum.
- If discontinued Riluzole, must have stopped it for at least 30 days.
- Able to swallow tablets. o Exclusion Criteria:
- Any other significant illness or significant abnormal laboratory values.
- Pregnant or breastfeeding women.
- History of dexpramipexole or currently on Pramipexole or other dopamine agonists.

Figures and Results

- 943 PALS enrolled.
- 474 randomly allocated to dexpramipexole, 468 to placebo and 01 withdrew.
- Least square mean CAFS scores at 12 months did not differ between groups:
- Dexpramipexole group score: 441.76 {95%}, CI 415.43-468.08. o Placebo group score: 438.84, 412.81-464.88; p=0.86.
- At 12 months follow-up, no differences in baseline ALSFRS-R:
- -13.34 for dexpramipexole group; -13.42 into placebo group; p=0.90. o Time to death (74 [16%] vs. 79 [17%] respectively. o Hazard ratio was 1.03 [0.75-1.43]; p=0.84).
- 37 (8%) PALS in experimental group developed neutropenia while, 8 (2%) in placebo.
- Incidences of adverse events were similar in both.

2.4. Literature Review on Efficacy and Safety of MCI-186: Edaravone for ALS28,29,30


- Study Type: Interventional Phase 3
- Allocation: Randomised Parallel Assignment
- Masking: Double Blind
- Location: Osaka, Japan
- Study Start Date: Dec 2011; Completion Date: Oct 2014
- Purpose: To confirm the safety and efficacy of 60 mg MCI-186 IV/OD in ALS, as per changes in ALSFRS-R after 24 weeks in double-blind, placebo-controlled manner.
- Edaravone

- The mechanism by which it’s effective in ALS is unknown. The drug is known to be an antioxidant and oxidative radicals have been hypothesised to be a part of process that kills neurones in PALS.
- T1/2, i.e. half-life of edaravone is 4.5 to 6 hours and of its metabolites are 2 to 3 hours.
- It is metabolised to a sulphate and a glucoronide conjugate, neither of which are active.
- It’s primarily excreted via urine as glucoronide conjugate form.

Material and Methods

- Primary Outcome Measures:
- ALSFRS-R improvement [Time Frame: 24 weeks]
- Secondary Outcome Measures:
- Time to death, from date of randomisation [Time Frame: 24 weeks]
- Time to any of following, from date of randomisation [Time Frame: 24 weeks]

- Inability to walk
- Failure of arm function
- Tracheostomy
- Respirator installation
- Tubal feeding
- FVC% deterioration [Time Frame: 24 weeks]
- Modified Norris scale score [Time Frame: 24 weeks]
- ALSAQ-40 [Time Frame: 24 weeks]
- Adverse events with lab tests. [Time Frame: 24 weeks]
- Fall in sensory examination. [Time Frame: 24 weeks]
- Arms And Assigned Interventions

- Experimental Arm: MCI-186 Edaravone in two cycles:-

- First cycle: Double blind phase: Two ampoules (60 mg) of MCI-186 IV/OD, for 14 days, followed by 14 days observation period. Cycle is repeated 5 times after first (2nd -6th cycles), i.e. Total 06 cycles.
- Second cycle: Observational cycle in open label phase: All patients on MCI-186 till 6th cycle can opt to continue from 7th until 12th at their will, or can choose for placebo instead.

- Placebo Comparator Arm: Placebo
- Similar dosage as for the experimental drug, under same double blinded randomised manner with patients’ consent and will.

Randomisation and Criteria

- Eligibility
- Ages : 20 Years to 75 Years
- Sexes: Both
- Accepts Healthy Volunteers: No
- Criteria

- Inclusion Criteria:

-"Definite ALS" or "probable ALS" as per revised EL Escorial.
- Can eat a meal, excrete, or move self without assistance.
- Less than 2 years since onset.
- ALS condition during past 12 weeks prior to enrolment too meets above requirements.

- Exclusion Criteria:

- Complications like Parkinson's disease, schizophrenia, dementia, renal failure, or any other severe complication.
- Hypersensitivity to edaravone.
- Pregnant, lactating, probably pregnant and who want to become pregnant and those who can’t agree to contraception.
- Participated in other trials within last 12 weeks before consent.
- Judged inadequate to participate by their physician.


- Dr. Palumbo et all studied 137 PALS with onset within 02 yrs.; with normal respiratory function, and were capable of daily activities.
- Patients received standard care, including Riluzole plus either edaravone or placebo.
- At 24 weeks follow-up, Edaravone was associated with lesser fall in ALSFRS-R (-5.01 vs. -7.50; difference between groups, 2.49; P = .0013).
- Also, edaravone group had lesser deterioration in QOL as per ALSAQ-40 (P = .03).
- No difference in grip strength between groups for no deaths in either.
- Additional 24-week open-label extension study among 123 patients from trial, in which all received the drug regardless of their initial assignment, showed a durable benefit of edaravone.
- Edaravone group recorded a lower risk of death (P = .019).
- Edaravone safety profile stayed good, with most common noticed issue of dysphagia in 12% PALS of experimental group.


- Major positive witnessed benefits in limb and bulbar scales with favours over respiration.
- Edaravone and placebo did’nt differ in adverse events, with contusion, dysphagia, and constipation predominating.
- The most common and serious side effect; was dysphagia.
- Trial reports have led to the approval of edaravone for ALS in Japan, marketed as Radicut.
- USFDA too granted edaravone the orphan drug designation31 for ALS.
- “We are not aware of any other positive phase III study in maybe a generation, since Riluzole, in ALS. So we are showing this data and we are hopeful that people are as excited as we are,” Dr. Palumbo.
- Radicava is an IVI administered with initial treatment cycle of daily dosing for 14 days, followed by 14-day drug-free span. Subsequent treatment cycles consists of dosing on 10 of 14 days, again followed by 14 days without the experimental medication..
- The most common adverse reactions reported by clinical trial participants receiving edaravone were bruising (contusion) and gait disturbance.
- FDA approval/201732:For Immediate Release May 5, 2017:-

“After learning about the use of edaravone to treat ALS in Japan, we rapidly engaged with the drug developer about filing a marketing application in the United States,” said Eric Bastings, M.D., deputy director of the Division of Neurology Products in the FDA’s Centre for Drug Evaluation and Research. “This is the first new treatment approved by the FDA for ALS in many years, and we are pleased that people with ALS will now have an additional option.”

- Radicava was seen to be leading to side effects like; hives, swelling or SOB.
- Allergy to sodium bisulphite, an ingredient in Radicava, may cause anaphylactic symptoms that can be life-threatening.


Major Neurostimulating Methods

3.1. Literature Review on CY4031-VIGOR-VITALITY-ALS; A Phase 3, Double-Blind, Randomised, Placebo-Controlled, Stratified, Parallel Group Study to Evaluate the Safety, Tolerability and Efficacy of Tirasemtiv in Patients with ALS34,35,36


- Study Start Date: August 2015; Completion Date: July 2017.
- Cytokinetics has developed Tirasemtiv (CK-2017357), a FSTA, as a potential option for PALS.
- Calcium is a pivotal regulator of muscle contraction; Tirasemtiv selectively activates fast skeletal MTC and increases calcium sensitivity leading to increased force and power with delayed fatigue.
- Aim: Tirasemtiv’s assessment (versus placebo), on measures of respiratory function and muscle strength in PALS.
- On October 2016, an open i.e. unmasked, clinical trial “VIGOR-ALS” began to assess long-term safety and tolerability of tirasemtiv, PALS who had completed VITALITY-ALS of 600 PALS.

Material and Methods

- Eligibility
- Ages: 18 Years and older
- Sexes: All
- Accepts Healthy Volunteers: No
- Experimental drug: tirasemtiv.
- Comparator Drug: Placebo.
- Primary Purpose: Treatment of ALS
- Groups:

- Comparator Group - Placebo
- Experimental Group 1 - 125 mg tirasemtiv
- Experimental Group 2 - 250 mg tirasemtiv
- Experimental Group 3 - 375 mg tirasemtiv
- Experimental Group 4 - 500 mg tirasemtiv o Schedule:
- Day 1 through Week 2 - 1 tablet of tirasemtiv and 1 tablet of placebo, BD.
- Weeks 3 through week 48 - 1 tablet of tirasemtiv and 1 tablet of placebo, BD, and 01 tablet of tirasemtiv extra in evening dosage.

- Study includes three phases:

- An open-label phase (2 weeks).
- A double-blind, placebo-controlled phase (48 weeks).
- A double-blind, placebo-controlled tirasemtiv withdrawal phase (4 weeks).

- Patients who can complete two weeks of treatment with open-label tirasemtiv 125 mg will be randomised 3:2:2:2 to placebo and three different dose levels of tirasemtiv.

Randomisation and Criteria

- PALS who entered study on stable Riluzole 50 mg BD, will continue at reduced dose 50 mg OD
- Inclusion Criteria:
- Familial or sporadic ALS < 24 months of screening.
- Upright SVC > 70 % predicted for age, height and sex.
- Able to swallow tablets during the trial.
- Laboratory findings within normal range else deemed “not significant” by Investigator.
- Either male patient must agree for the study and 10 weeks, to use condom during intercourse with female partners of childbearing potential and to have female partners use additional contraception, or he must agree to abstain from intercourse during and for 10 weeks after the study, unless has had a vasectomy with confirmed sperm count of 0.
- Female patients must be post-menopausal (> 1 year) or sterilised, or, if of childbearing potential, not breastfeeding, have negative UPT with no intention to become pregnant during study and use effective contraceptive devices while requiring male partner to use condom during and 10 weeks after trial ends.

- Exclusion Criteria:

- At the time of screening, using NIV/BiPAP for any portion of the day, or mechanical ventilation via tracheostomy, or on any oxygen supplementation. o Patients with DPS at entry or who anticipate DPS placement during. o BMI of 20.0 kg/m2 or lesser.
- Unable to discontinue tizanidine and theophylline medications during participation.
- Serum chloride outside normal range.
- Clinical laboratory findings deemed clinically significant by Investigator.
- Any neurological impairment other than ALS, inclusive of TIA within a year.
- Any significant cardiac, pulmonary, GI, musculoskeletal, or psychiatric illness that interfere with capability to follow procedures or deviates interpretation of safety or efficacy data, including but not limited to:

- Poorly controlled hypertension.
- NYHA Class II or greater.
- COPD or asthma requiring daily bronchodilators.
- GI disorders impairing study drug’s first pass metabolism.
- Significant liver disease as per bilirubin over twice the normal or ALT/AST >3 times on repeat testing.
- Poorly controlled DM.
- History of vertigo, unexplained syncope or uncontrolled epilepsy within three months of entry.
- History of untreated intracranial aneurysm.
- Limb amputation.
- Cognitive impairment effecting patient's ability for consent or to comply with study procedures.
- Cancer with metastatic potential (other than BCC, CIN or SCC excised with clean margins) diagnosed and/or treated within last 2 years.
- Judged to be actively suicidal or at risk by Investigator.
- Had any investigational drug within 30 days or five half-lives of agent, whichever is greater, prior to dosing.
- Prior participation in stem cell therapy for ALS.
- Previously received tirasemtiv.

- Primary Outcome Measures :

- Change in predicted SVC%. [Time Frame: 24 weeks]

- Secondary Outcome Measures :

- Time to first decline from baseline in predicted SVC
- 20% or respiratory insufficiency or death [Time Frame: 48 weeks]. o Time to first decline in SVC to
- 50% predicted or respiratory insufficiency or death [Time

Frame: 48 weeks]. o Time to first mechanical ventilatory assistance or death [Time Frame: 48 weeks]. o Time to first decline in respiratory components of ALSFRS-R (i.e., items 10, 11, and 12) or death [Time Frame: 48 weeks].

- Change in muscle strength mega-score [Time Frame: 24 wks.]. Figures and Results
- No study results posted for this study.
- Study status: On-going, but not recruiting.
- Estimated Study Completion Date: July 2017 (for VIGOR, coming from VITALITY)
- Enrolment: 743

3.2. Literature Review on Multi-Centre, Randomised Controlled Study of NeuRx ® Diaphragm Pacing System™ In Participants with Als


- Status: Currently Recruiting42
- Study Start Date: August 2013. Completion Date: April 2017
- Purpose:

- To assess if DPS prolongs life and maintains QOL when given as adjuvant to standard care, i.e. If DPS in PALS is associated with improved survival.
- Primary objective:- Multi-centre, randomised controlled clinical trial to compare standard of care to diaphragm stimulator assisted treatment with “NeuRx® Diaphragm Pacing System™ (DPS)”, for scaling survival in PALS.
- Secondary objective: - Compare standard of care to DPS in subjects of respiratory lag.
- Although it’s uncertain before trial if DPS is efficacious, given the preliminary studies by device manufacturer, it has received FDA HDE approval as HUD and implemented in guidelines45.

Material and Methods

- Treatment Type: Device: NeuRx® Diaphragm Pacing System™ (dpstmTM)
- Trial Type: Interventional Phase 2
- Study Allocation: Randomised as 2:1
- Intervention: Parallel Assignment
- Masking: Open Label
- Primary Purpose: Supportive Care (Not treatment)

Randomisation and Criteria

- 2:1 randomisation schedule such that, 2/3rd chance of receiving DPS and 1/3rd for standard of care (control) treatment.
- Enrolment Criteria:

- Breathing ability without assistance at entry.
- FVC or SVC of 50-75% of predicted or better.
- PALS won’t use BiPAP in trial and must agree to it.
- DPS availability
- PALS accessible to following locations:

- Derriford Hospital, Plymouth, PL6 8DH
- St James University Hospital, Leeds, LS9 7TF
- Royal Free Hospital, London, NW3 2QG
- University Hospital of South Manchester, Manchester, M23 9LT
- Royal Victoria Infirmary, Newcastle-Upon-Tyne, NE1 4LP
- John Radcliffe Hospital, Oxford, OX3 9DU
- Royal Hallamshire Hospital, Sheffield, S10 2JF

- Eligibility:

- Age: 21 years and older
- Laboratory-supported probable, probable or definite ALS.
- Genders: Both
- Not accepting healthy volunteers.

- PALS randomised to have NIV alone or DPS in addition to NIV.
- They need to complete outcome measures at 5 follow up points (2, 3, 6, 9 and 12th month).
- DPS group will have additional visits for surgical DPS removal and a week post-op follow up.
- 12 patients from DPS group also set to complete 2 qualitative interviews.
- Primary Outcome Measures:

- Survival [Time Frame: 18 months](later changed to Supportive Care.)
- Secondary Outcome Measures:
- QOL [Time Frame: 18 months]
- Arms and Assigned Interventions:
- Experimental arm

- NeuRx® Diaphragm Pacing System™ (DPS) device43.
- Under GA; IM electrodes were laparoscopically implanted in diaphragm with ends being tunnelled subcutaneously over chest or abdominal wall and connected to an external stimulator.

- Standard of care arm
- Patients won’t have DPS but will receive ALS standard care.
- Criteria
- Inclusion:
- Age 21 years or older.
- Sporadic or familial ALS of definite, probable or possible ALS as per revised El Escorial criteria44.
- Any sign of hypoventilation at screening with any or all of following:
- MIP <60 cm H20.
- FVC <50% predicted for gender, age and height.
- Recordable phrenic nerve potential bilaterally.

- Shouldn’t have Riluzole for 30 days or on stable dose for at least 30 days, prior to randomisation. Riluzole-naïve subjects are also permitted.
- Capable for consent.
- Accessible to trial site.
- Negative UPT at screening in females of reproductive age.
- Female of child bearing potential must use adequate contraception:

- Abstinence or hormonal contraception (oral / implanted / injected / other patch or contraceptive ring)
- IUCD in place for > 3 months
- Barrier method in conjunction with spermicide. o Exclusion:

- Upright FVC < 45% predicted for gender, age and height.
- History of NIV outside of sleep.
- Pulmonary or cardiac disorder or other diseases that could be a contraindication for GA or DPS implant.
- Any implanted device of magnetic or electrical nature like pacemaker or ICD.
- Any diaphragm abnormality like hiatal or para-oesophageal hernia.
- Participation in another research for PALS within 30 days of screening visit.
- Significant history of unstable or severe cardiac, oncologic, hepatic, psychiatric, renal or other significant illness.
- Pregnant or currently breastfeeding.


- From Dec 5’2011 and Dec 18’2013; randomly assigned 74 participants to receive either NIV alone (n=37) or NIV plus DPS (n=37).
- On Dec 18’2013, DMEC suspended recruitment on basis of survival figures and asked to continue for supportive care as primary purpose.
- Assigned PALS continued as per protocols till June 23’2014, afterwards DMEC asked for discontinuation of pacing.
- Follow-up scheduled as planned till December 2014.
- Shorter survival in experimental group than in the NIV alone group (median 110 months [95% CI 8 3–13·6] vs 22·5 months [13·6-not reached]; with an adjusted hazard ratio 2·27, 95% CI 1·22-4·25; p=0009).
- 28 (76%) deaths in pacing group while 19 (51%) in control group.
- Noticed 162 negative impacts (5·9 events per person-year) in NIV+DPS group, of which 46 were serious.
- There were 81 downsides (2 ·5 events per person-year) in NIV alone group, including 31 concerning ones.


- Background NIV is the part of ALS standard care for helping respiratory failure.
- Nurex dpstm addition to above was found hazardous to survival in PALS.
- Results proved that DPS shouldn’t be used for SOB in PALS.
- FDA has approved this device for the age of 21 and above only.
- FDA Approval Order Statement45,46; “This device is indicated for use in PALS with a stimulant able diaphragm (both side) as demonstrated by voluntary contraction or phrenic nerve conduction studies, and who are experiencing hypoventilation, but not progressed to an FVC < 45% of predicted.”

3.3. Literature Review on Repetitive Trans cranial Magnetic Stimulation (rTMS) in Amyotrophic Lateral Sclerosis (rTMS-ALS)


- Enrolment: 20
- Study Start Date: May 2007; Completion Date: December 2008
- Study Type: Interventional
- Allocation: Randomised
- Intervention: Parallel Assignment
- Masking: Double Blind
- Locations - Institute of neurology, University of Cattolica, Rome, Italy
- Several studies have suggested that rTMS may have positive benefit in ALS. However, efficacy and safety of it is yet to ascertain.
- Aim: Efficacy of rTMS as supportive care with safety concerns in ASL.

Material and Methods

- rTMS:- Method to excite nerve cells in superficial areas of brain using pulsed magnetic fields of cTBS via an electrode over scalp for motor cortex hyper excitability with BDNF release.
- Purpose
- The investigators' preliminary studies demonstrated that rTMS may determine a slight slowing in the rate of disease progression in ALS49. o Aim: Investigate if rTMS of motor cortex over a long period (12 months) in a group of PALS, can have pronounced beneficial and non-damaging effects. o Compared the disease progression in 2 groups of patients:

- First group:- Received real rTMS (a week daily treatment per month)
- Second group:- Given sham rTMS (placebo).
- Primary Outcome Measures: Rate of decline in ALSFRS-R [Time Frame: 1 year]
- Secondary Outcome Measures: Rate of decline in MMT(s) [Time Frame:1 year]
- Arms & Assigned Interventions

- Active Comparator: A

- Patients receiving real rTMS.
- rTMS performed using a focal coil over motor cortex of both hemisphere, one by one.
- Stimulation protocol was cTBS; three pulses of stimulation at 50 Hz, repeated every 200 micro second for a total of 300 pulses delivered over each motor cortex. (i.e.“3pulses@50Hz”/200ms: 100 times)
- Stimulus intensity was set at 80% of AMT. o Sham Comparator: B
- Sham rTMS was involved with same stimulator using placebo butterfly coil MCF-P-B-65 which had no cortical stimulating effect but produces similar auditory and tactile sensations as of active coil.
- Site of stimulation and protocols were identical to those used for active rTMS.

Randomisation and Criteria

- Eligibility
- Ages: Child, Adult, Senior (ALL)
- Sex: All
- Accepts healthy volunteers: No
- Criteria
- Inclusion Criteria:
- A diagnosis of definite ALS according to El Escorial(R) criteria with clear clinical UMN and LMN signs.

- Exclusion Criteria:

- Contraindications to rTMS:
- Tracheostomy
- Pacemaker/ICD
- Implanted metallic devices
- Epilepsy
- Unexplained syncope/ TIA within 1 year of screening
- Consent issues due to impaired cognition.


- Rate of decline in ALSFRS-R for both, active and sham patients deteriorated during treatment, with a significant difference in TIME [F (5, 13) = 68.67; P < 0.0001].
- Two-factor analysis of variance revealed a significant TIME ×TREATMENT interaction [F (1, 5) = 5.16; P = 0.0005], due to slower deterioration rate in active rTMS group.
- Post hoc PLSD analysis showed a significant difference between active and sham patients at last control (P = 0.035).
- The rate of decline in MMT for both groups had significant effect of TIME [F(5, 13) = 25.9; P < 0.0001]. Two-factor analysis of variance showed a significant TIME×TREATMENT interaction [F(1, 5) = 2.43; P = 0.044], because active rTMS had slower deterioration rate.
- MVIC of hand for active and sham PALS deranged in trial with noticeable effect of TIME [F(5, 13) = 8.76, p < 0.05]. In two-factor analysis of variance, no significant difference between groups [F (1, 5) = 0.76, p > 0.05].
- Two-factor analysis had no recordable variance in BDNF plasma levels between both set of patients [F (1, 1) = 0.66; p > 0.05]. Mean BDNF plasma in baseline was 3682±791 pg/ml in active and 3553±223 pg/ml in sham PALS, after a 5 day cycle of daily cTBS.
- Mean BDNF plasma level in active group was 4036±782 pg/ml and 3179±1800 pg/ml in sham.


- By the end of trial, patients were asked to guess out if they had real or sham stimulation.
- Statistical analysis was done by two-factor repeated measure analysis of variance (TIME and TREATMENT).
- Post hoc Fisher’s exact PLSD analysis for; finger and joint type, grasp posture and device type was achieved using significance value of 0.
- 1 active patient refused to participate after first day of the first cycle due to traveling issues.
- 1 active patient quit for unrelated condition (breast cancer), 2 months after enrolment.
- 1 sham patient developed Ileus (unrelated), 2 months after treatment initiation and died.
- 1 sham patient died of respiratory failure (ALS related) 4 months after day 01.
- 1 active patient got enrolled in different trial 4 months later and hence excluded.
- Overall, 15 patients (7 active and 8 sham) were included in 6-months analysis.
- Clinical, demographic and electrophysiological results of these 15 PALS are briefed as:-

- 01 patient from each group had no first dorsal interosseous motor evoked potential on stimulation of a hemisphere, with preserved response of counter side. Thus, “central motor conduction time” and AMT couldn’t be scaled on previous side.
- Central motor conduction time: -

- Of first dorsal interosseous was within normal limits in 01 PAL of either arm.
- Bilaterally above the normal limits (>7.7ms) in two sham and two real patients.
- Either mono laterally prolonged or showed pathological difference (>1ms) in 04 real and 03 sham patients.

- Active motor threshold:-

- Within normal limits in 02 real and 03 sham patients.
- Bilaterally above normal limits (>57% of maximum stimulator output) in 03 real and 02 sham patients.
- Above normal limits on a side in 01 real and 02 sham patients.
- rTMS was well tolerated by patients without any side effects.
- All participants believed that they had real stimulation, as even real TBS was below motor threshold; hence main sensation perceived by group was local.
- Sham and real stimulation were similar in auditory and tactile sensations, making it impossible to distinguish between the two forms..
- Other measures had no difference between real and sham rTMS with respect to ALSFRS-R or MMT at 12 months follow-up.
- No disability or limitation, assessed by ALSFRS-R at 06 months follow-up, the primary measure of effectiveness of rTMS, was noted.

Chapter 4: Critical Analysis

1. Critical Analysis on Controlled Trial of Riluzole in Amyotrophic Lateral Sclerosis

- Riluzole had significant effect on the rates of survival and muscular deterioration in this randomised, stratified, double-blind, placebo-controlled study of 155 patients with ALS.
- We chose survival as a primary end point so as to distinguish possible efficacy from symptomatic effect on function that didn’t reduce motor-neuron loss.
- The effect of treatment on survival at 12 months remained significant after we controlled for other risk factors in a Cox proportional-hazards analysis.
- The favourable effect of Riluzole on survival seems to depend on the site of onset of disease. A large and significant effect was observed in bulbar onset, whereas in those with limb onset only a trend toward positive effects was detected. Clearly, Riluzole was less effective in patients with limb-onset disease, but at this point we cannot precisely account for the differences with respect to the pattern of onset. Such a striking difference must be interpreted carefully because, as Peto19 has pointed out, such an effect can arise by chance.
- Therapeutic effect of Riluzole seems to be time-related, as strong effect observed in first 12 months and an apparent fall in effect from month 12 to month 21 (placebo-controlled period).
- The higher rate of withdrawal from Riluzole group may have led to an underestimation of actual benefit from the drug, since we used an intention-to-treat analysis.
- To summaries
- Adverse reactions don’t outweigh the therapeutic effect on survival, though worsen the QOL but such consequences may be outweighed by the effects on muscle function.
- Riluzole has a positive effect on rate of deterioration of muscle function, suggesting that it may interfere with motor-neurone degeneration even though mechanism of action remains unclear.
- Statistical Analysis
- Performed with intention-to-treat basis and included all randomised PALS.
- Continuous variables for demographic data and clinical values at entry were compared by “two-way analysis of variance” using assigned treatment, site of onset and interactions between them.
- Qualitative variables compared by chi-square tests.
- Survival curves of groups were compared by Mantel-Cox log-rank12 , stratified as per site of onset.
- Prognostic factors determined by Cox proportional-hazards analysis13 stratified as above.
- Effect of treatment on survival also assessed with by Wald’s test14.
- The clinical scores over time were estimated using least-squares method. Factors included were, treatment (Riluzole vs. placebo), site of disease onset and interactions of both.

2. Critical Analysis on Clinical trial with ceftriaxone in amyotrophic lateral sclerosis

Though this trial had been a randomised double blinded study with good number of patients of ALS, which was a huge count of 600, the benefits in stage three lacked all desired primary or even secondary outcomes, decided prior to stage 01, i.e. start of the trial. It was performed with intention-to-treat basis and included all randomised PALS. Demographic and clinical values at the entry were compared using analysis of variance and chi-square test was used for comparing qualitative variables. The clinical scores over time were estimated using least-squares method.

During stage 1 and 2, mean ALSFRS-R declined more slowly in participants on 4 gm. ceftriaxone than those on placebo (difference 0.51 units per month, 95% CI 0.02 to 1.00; p=0.0416), but during stage 3, functional decline between groups didn’t differ (0.09, -0.06 to 0.24; p=0.2370). No difference in survival recorded in stage 3 (HR 0.90, 95% CI 0.71 to 1.15; p=0.4146) as well, with GI and hepatobiliary adverse events reported more in ceftriaxone group (GI- 245 [72%] ceftriaxone vs. 97 [56%] placebo, p=0.0004. Hepatobiliary- 211 [62%] vs. 19 [11%], p<0.0001).

Interpretation we can squeeze would be that, despite hopeful stages of 1 and 2; the stage 3 of “ceftriaxone in ALS” didn’t prove efficacy or safety on long term dosage, demanding further trials of ceftriaxone in combination with measures to minimise previously seen side effects, or; current trial’s modification in exclusion and inclusion criteria with higher range for normal hepatic functions might solve the issue, else also it will be at least beneficial as being informative to future researchers.

3. Critical Analysis On Randomised, Double-Blind, Placebo-Controlled, Study of Safety and Efficacy of Dexpramipexole in Subjects with ALS

Dexpramipexole is generally well tolerated, but few PALS under experimental room developed neutropenia, supposedly an expected but rare side effect, expected as per its pharmacodynamics and pharmacokinetic properties.

Even after being a powerful study of; huge “n” involved, which was 943 (roughly 1000), with randomised double blinded efforts with no room for biasness, the primary endpoint of CAFS wasn’t achieved. The research was performed with ‘intention-to-treat’ basis, inclusive of qualitative variables compared by chi-square tests. No difference from placebo on any pre specified efficacy endpoint measurement, seen in dexpramipexole group.

After conferring mitochondrial stress protection in neuronal cells, drug deprived the anticipated help for PALS, as evident with respect to reports on desired end points of respiratory function and survival, hence the results of this trial; don’t argue positively for future studies of RPPX in ALS. In addition to the negative outcome for primary concern(s), secondary objectives also weren’t touched with a side effect of significant issue in minor counts (8%), even if other downsides were similar with respect to placebo.

4. Critical Analysis on Efficacy and Safety of Edaravone for ALS

Edaravone confers neuroprotection via free radical-scavenging activity, it’s for the treatment of ALS was demonstrated in a six-month clinical trial conducted in Japan.

Accounting 137(n) participants were randomised for edaravone or placebo, and at week 24, edaravone declined less on assessment of daily QOL compared to placebo. The number of involved cases i.e. “n” wasn’t in range of 500s or 1000s, yet it’s an amazing count favouring towards a strong trial conducted in Japan.

As per reports published, none of the patients inclusive of experimental group were off the standard ALS care, and Edaravone was an additional element, rather than being main or competitive. Not only the main objective was ticked green, but also there were mentionable scaled secondary issues being accomplished, in this double blinded randomised local trial, reciprocating antioxidant edaravone’s association with lesser deterioration in functional rating and QOL if started earlier.

USFDA has granted Edaravone, an orphan drug designation, which provides incentives to assist and encourage its development. U.S.FDA has also approved Radicava (edaravone) to treat PALS, with continuation of its previous use for TIA globally, i.e. After this vital and milestone trial, ALS also has been included into Edaravone utility.

According to Dr. Joseph M. Palumbo33, head of clinical research at Mitsubishi Tanabe Pharma Development America, the maker of Edaravone; it’s now been approved in several countries for ALS and TIA both.

5. Critical Analysis on CY4031-VIGOR-VITALITY-ALS (Tirasemtiv)

Tirasemtiv activates the fast skeletal MTC and increases its sensitivity to calcium, leading to increased isometric contractile force and power with delayed time to muscle fatigue. Aforementioned mechanism hence helps in ALS with symptomatic relief than being modulator of disease progression.

The number of patients (n), enrolled into the trial is huge, and initial double blinded randomisation of VITALITY, and then continuation of previous successful participants into open labelled randomised VIGOR, makes this binary tracked and dual tested trial, amongst most successful ones statically, whatever the result is unveiled in future. The efforts were put with ‘intention-to-improve respiratory symptoms’, than usual ‘intention to treat’. The qualitative variables compared by chi-square test and drug’s fate in ALS perspective are subjective to next scheduled; or better to say for current times, the second and running trial results.

Huge list of inclusion and exclusion criteria again add up into the statistics, making outcome not just of more specificity value but also sensitivity. A follow up of 24 weeks and inclusion of Riluzole naïve to Riluzole running patients, is something unique and worth noticing here, which made this study not just double blinded from experimental drug prescription level, but also reduces the probability of biasness from previous medications for ALS history.

I think, in coming months, as the results of these two trials published in conjunction, with a focus of pre-determined primary and secondary objectives, there won’t be any need of further cross examination, due to such rules and regulations tightened around the ‘dual-research’, with one of its controlled trial being already executed and analysed.

6. Critical Analysis on Study of NeuRx ® Diaphragm Pacing System™ In Participants with ALS

Diaphragm, a well-known and vital component of respiratory ‘bucket-handle’ mechanism, is one of the chief victims in ALS, and any stimulation of electric, chemical or physical nature can help the patients from point of SOB and appetite symptoms; but in this study, primary concerns were scaled on a follow up pattern; rather than immediate support and feeding.

Patients, carers and outcome assessors weren’t masked leading to paths for bias ness in data. Primary outcome was survival, defined as the time from randomisation to death from any cause with analysis being under ‘intention to treat’. Later the primary outcome of “survival figures” changed to “supportive care”, as instructed by DMEC.

All procedures under this multi-centre open, unmasked, randomised controlled trial were at 07 ALS and respiratory specialist centres in UK. The enrolment was though just a double digit count in 70s as mentioned in literature review of research reports, but for a primary purpose of “supportive care” than treatment, and a trial for proving something already into guidelines under exceptional grounds of immediate effects on breaths and food, I personally find it to be an extremely significant “n”.

Due to the lack of double blinded-ness, the study reports of this open label trial can’t be unbiased, and hence I think, should be referred and interpreted cautiously. All eligible participants of 21 years or over with lab supported probable, clinically probable or clinically definite ALS, with significant but lesser criteria of exclusion than inclusion further adds into chance of biasness. Also the participants were randomly assigned as “2:1” via centralised web-based randomisation system with minimisation that balanced patients for age, sex, FVC% and bulbar function, to receive either “NIV plus pacing with NeuRx RA/4 DPS vs. NIV alone”; in place of “1:1” randomisation, which could again be associated with biased outcome weighing on experimental side on results. The experimental group had lesser survival figures with adjusted hazard ratio of 2•27, 95% CI 1•22-4•25; p=0•009. About 75% deaths were seen in experimental arm with huge gap when compared with control having about 50%. Also 162 side effects seen in combination group, and only 81, i.e. half of trial arm in the control group.

Immediate positive clinical betterment in symptomatically lagging fatigued diaphragm and condition’s relief; when combined with negative feedback from aforementioned bias probabilities on test results might have again favoured the HDU approval of DPS with NIV, in the eyes of FDA and European guidelines too.

7. Critical Analysis on rTMS-ALS

The pros of rTMS-cTBS should be balanced against cons of taking part in trials for PALS. In this publication, due to small “n” i.e. number of patients, results of this study should be cited cautiously. This small controlled trial showed a qualitative decline in ALS due to cTBS of motor cortex as scored with ALSFRS-R and MMT. Minute gap between active and sham patients became evident after few months and attained significance only by last control, pointing towards the need of further trials for inclusion of rTMS under standard of care, or even as symptomatic add on management option.

For now, the limited PALS registration with environmental factors like unrelated medical issues and co-parallel different trial involvement, further lowering “n”, has urged a need of another trial of similar technology; conducted with additional exclusion criteria and multi ethnic and multi continental approach. Even after being a powerful double blinded parallel assigned randomised trial, the pits of small “n”, tiny and generalised inclusion criteria and very restricted exclusion rules have made this trial thirsty for reopening and reprocessing whole events with additional factors added into respective areas to make it more countable, as a strict and durable study.

The current value of this study is held by the fact that, a new outlook or vision can be appreciated for the management of ALS, and such step towards magnetism for ALS via electrodes, does attract the need of studying this one with keen eye for next trial, because:

- N=20, which is far small count.
- There were immediate benefits for sure, even if not documented in follow up scores.
- It could be beneficial in some other frequency than the one used here and location of excitation can be reset juxta occipitally.
- We need to be optimistic with rTMS because, as already witnessed the DPS which had symptomatic relief so bold that even with failed follow-up reports, it made an exceptionally beneficial humanitarian device.

CHAPTER 5: Conclusions and Future Scope

5.1 Conclusions:

Following diagram has been drawn to help us encapsulate all the aforementioned facts in brief; the diagram has been developed by me to illustrate:

- Various major mechanisms for ALS, including both; pathophysiology and aetiology with link between them.
- Management option with their respective mechanisms to help in ALS.

Abbildung in dieser Leseprobe nicht enthalten

Overall, ALS management updates follow its pathway from mechanism to effects; at various levels. On one hand there’re drugs that suppress the glutamate levels in CNS while on other side free radical scavenging chemicals which hamper the secondary pathogenesis. During thesis we have also encountered the therapies of improving the effects of lag in ALS out of increased nerve cell injuries and also various stimulation technologies.

There’re also some options developed aiming neo genesis of damaged nerves for disease reversal, which aren’t included into this dissertation, either due to their extreme recent chronology or lack of sufficient data projections; but I’ve mentioned them into oncoming section of future scope.

To summarise for now, all the researches and human trials have following essence;

1. Riluzole is till the only drug with confirmed ‘glutamate lowering potential’ and supposed unknown mechanism in some case causing significant anti ALS- progression.
2. Ceftriaxone, dexpramipexole, edaravone, tirasemtiv, dpstm and rTMS, have their respective pros and cons as discussed in research trials done, with roughly half of them accepted and approved for use as complement to Riluzole, while remaining have fallen into the section desiring further efforts by doctors and researchers.

Few spotlight advancements yet under development, but worth at least mentioning; are also put up into next section. They do deserve a keen outlook alongside rest of the study details with respect to futuristic vision. Overall juice, which is the ultimate answer to our primary query of perfect management for ALS would be an emptiness, because none of developments till date have proven to be efficient enough, demanding a combined approach of NPMs and NSMs, in proportions as required, per case.

For such ancient disease giant, researched management options are even bifurcated into two perspectives, based on their efficacious results:-a. QOL, i.e. quality of life, which basically reflect as signs and symptoms associated. b. Quantity of life, i.e.; survival or average lifespan once ALS is diagnosed. 07 clinical trials have been chosen by me out of many as per their respective success or capability of modifying guidelines in coming future of PALS standard of care. For comprehensiveness, I’ve divided them into two main streams of being “Neuroprotective” or “Neurostimulating”, than being listed haphazardly; under self-created management classification system called “TOS-ALS” for “Therapy Options Classification system for ALS”.

Neuroprotective Methods, aka “NPMs”, are any procedure or medication or lifestyle modification that stops or lower the rate of further nerve damage by ALS, and includes:-

- Glutamine acid release inhibitor Riluzole. It was the only drug for 20 long years since 1992, till other options developed.
- Glutamate to glutamine reaction catalyst Ceftriaxone.
- Mitochondrial salvation by Dexpramipexole.
- Free radical scavenger antioxidant Edaravone. Neurostimulating Methods, aka “NSMs”, includes any therapy for complementing the lag in various neuromuscular functions due to ALS:-
- Tirasemtiv, yet under trial for results.
- DPS, which is into practice and witnessed by me personally during my training period.
- rTMS, analogues to DPS from employment perspective of stimulation, though aiming cortex in brain unlike local muscle fibres and neuro muscular junction (NMJ) in DPS.

5.2 Future Scope

- Few more efforts that worth mentioning, though not included in this thesis, but holds many cards in coming times, and demands a keen explorative view:-
- Tocilizumab51,52: Though not an initial cause of ALS, the immune system has a role in death of motor neurons by interleukin-6 (IL-6) whose effect is blocked by this and thus may slow the disease. o Ezogabine (retigabine)53,54,55: Neuronal hyper excitability contributes to neurodegeneration ALS. It s required to determine how K channel opener Ezogabine affects neurophysiological measures of UMN and LMN excitability in PALS as assessed by TMS and TTNCS. o Convert human skin cells into motor neurons, i.e., Neuronal Subtype-Specific Reprogramming of Adult Human Fibroblasts56,57,58,59,60: Reprogramming of human fibroblasts into fully differentiated neurons by induction of a chromatin environment permissive for acquiring neuronal subtype identity. The brain-enriched miRNAs; miR-9/9 and miR-124 trigger reconfiguration of chromatin accessibility, DNA methylation, and mRNA expression to induce a default neuronal state. miR-9/9 and miR-124- induced neurons (miNs) are functionally excitable and possess open chromatin at neuronal subtype specific loci, suggesting a modular synergism between miRNAs and neuronal subtype-specific transcription factors.

CHAPTER 6: References


2. A Controlled Trial of Riluzole in Amyotrophic Lateral Sclerosis G. Bensimon, L. Lacomblez, V. Meininger, and ALS/Riluzole Study Group.

3. N Engl J Med 1994; 330:585-591March 3, 1994. DOI: 10.1056/NEJM199403033300901

4. Swash M, Leish N. Criteria for diagnosis of familial amyotrophic lateral sclerosis: European FALS Collaborative Group. Neuromuscul Disord 1992;2:7-9

5. Brooks BR, Sufit RL, DePaul R, Tan YD, Sanjak M, Robbins J. Design of clinical therapeutic trials in amyotrophic lateral sclerosis. Adv Neurol 1991;56:521-546

6. Lacomblez L, Bouche P, Bensimon G, Meininger V. A double-blind, placebo-controlled trial of high doses of gangliosides in amyotrophic lateral sclerosis. Neurology 1989;39:1635-1637

7. Jablecki CK, Berry C, Leach J. Survival prediction in amyotrophic lateral sclerosis. Muscle Nerve 1989;12:833-841

8. Norris FH, Denys EH, Sang K, Mukai E. The natural history of ALS in a specified population, with comments on risk factors, prognosis and symptomatic treatments. Clin Neurol1989;29:1485-1492

9. Caroscio JT, Mulvihill MN, Sterling R, Abrams B. Amyotrophic lateral sclerosis: its natural history. Neurol Clin 1987;5:1-8

10. Kondo K, Hemmi I. Clinical statistic in 515 fatal cases of motor neuron disease. Neuroepidemiology 1984;3:129-148

11. Bensimon G, Rozier A, Dib M, Lacomblez L, Bouche P, Meininger V. Variables influencing the functional loss and the rate of evolution in amyotrophic lateral sclerosis. Neurology1992;42:Suppl 3:202-202 abstract.

12. Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 1966;50:163-170

13. Cox DR. Regression models and life-tables. J R Stat Soc [B] 1972;34:187-220


15. Mizoule J, Meldrum B, Mazadier M, et al. 2-Amino-6-trifluoromethoxy benzothiazole, a possible antagonist of excitatory amino acid neurotransmission -- I. Anticonvulsant properties. Neuropharmacology 1985;24:767-773

16. Martin D, Thompson MA, Nadler JV. The neuroprotective agent riluzole inhibits release of L-glutamate and L-aspartate from slices of hippocampal area CA1. Br J Pharmacol1991;104:Suppl:240P-240P abstract

17. Benoit E, Escande D. Riluzole specifically blocks inactivated Na channels in myelinated nerve fibre. Pflugers Arch 1991;419:603-609

18. Doble A, Hubert JP, Blanchard JC. Pertussis toxin pretreatment abolishes the inhibitory effect of riluzole and carbachol on D-[3H]aspartate release from cultured cerebellar granule cells. Neurosci Lett 1992;140:251-254

19. Peto R. Statistical aspects of cancer trials. In: Halnan KE, ed. Treatment of cancer. London: Chapman & Hall, 1982:868-71

20. Northeast ALS Consortium Stage III Trial of Ceftriaxone;


22., November 2009 (First received: July 5, 2006)

23. NCT00349622 clinical trial with ceftriaxone in subjects with amyotrophic lateral sclerosis (ALS). Other study IDs include: U01NS049640-02, NINDS, U01NS049640-02, NINDS CRC.

24. Sponsor and Collaborators: Massachusetts General Hospital (Merit E. Cudkowicz, MD), National Institute of Neurological Disorders and Stroke (NINDS)

25. Phase 3 Study of Dexpramipexole in ALS (EMPOWER), DOI:|

26. A randomised, double-blind, phase 3 trial. Identifier: NCT01281189. Other Study ID Numbers: 223AS302, EUDRA CT NO: 2010-022818-19

27. Sponsors and Collaborators- Knopp Biosciences

28. Phase 3 Study of MCI-186 for Treatment of ALS

29. Sponsor: Mitsubishi Tanabe Pharma Corporation.

30. Id: NCT01492686 ( Other Study ID Numbers: MCI186-19

31. FDA Orphan Drug Act 1984

32. Fda approval;

33. Head of Clinical Research at Mitsubishi Tanabe Pharma Development America, the maker of edaravone.

34. Identifier: NCT02496767,

35. Study Director: MD Cytokinetics;

36. EudraCT Study ID Numbers: CY 4031, 2014-005413-23

37. ID: NCT01938495

38. Sponsor: Sheffield Teaching Hospitals NHS Trust, Barrow Neurological Institute

39. Primary Investigator: Dr. Christopher McDermott: 01142220717;

40. Registered ISRCTN number 53817913.

41. Further study details as provided by Jeremy Shefner, Barrow Neurological Institute.

42. ALS Forum, ALS Association, Muscular Dystrophy Association, Synapse Biomedical.

43. The NeuRx® Diaphragm Pacing System™ (DPS) is a four channel, implanted percutaneous diaphragm muscle stimulation system provided by Synapse Biomedical, Inc. ID; NCT00010374 and NCT00420719

44. Swash M, Leish N. Criteria for diagnosis of familial amyotrophic lateral sclerosis: European FALS Collaborative Group. Neuromuscul Disord 1992;2:7-9

45. FDA Orphan Drug Act 1984

46. NurexDPS HDE No. H100006/09/28/2011; advised by Anaesthesiology committee: “Approval of Nurex dpstmTM”

47. Sponsor: Catholic University of the Sacred Heart.

48. Identifier: NCT00833820. Other Study ID Number: 001

49. Motor cortex stimulation for ALS: a double blind placebo-controlled study. Neurosci Lett. 2009 Oct 16;464(1):18-21. doi: 10.1016/j.neulet.2009.08.020. Epub 2009 Aug

50. KNS-760704 was originally identified as a candidate therapy for ALS by James Bennett, M.D., Ph.D., then of The University of Virginia.


52. Tocilizumab (Actemra™) IV infusion, ALS Association, Barrow Neurological Foundation, Massachusetts General Hospital, Genentech, Inc.

53. Collaborators: ALS Association, GlaxoSmithKline, Harvard University, Massachusetts General Hospital.

54. Information provided by (Responsible Party): Brian Wainger, Massachusetts General Hospital

55. Identifier: NCT02450552

56. DOI:; Published: September 7, 2017

57. Daniel G. Abernathy, Woo Kyung Kim, Matthew J. McCoy, Allison M. Lake, Rebecca Ouwenga, Seong Won Lee, Xiaoyun Xing, Daofeng Li, Hyung Joo Lee, Robert O. Heuckeroth, Joseph D. Dougherty, Ting Wang, Andrew S. Yoo

58. Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA

59. Program in Developmental, Regenerative, and Stem Cell Biology, Washington University School of Medicine, St. Louis, MO 63110, USA



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Neuroprotective vs. Neurostimulating Management Options for Amytrophic Lateral Sclerosis. A Multiple Trial Based Comparison
University of Buckingham  (Ealing Hospital London)
Doctor Of Clinical Internal Medicine (MD)
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ACKNOWLEDGEMENT I express sincere gratitude to my supervisor, Dr. Vijay Mangalam for guiding me throughout the student life here and offering me guidance and resources for pursuing my degree. I would also like to thank following, for their guidance and support throughout the course: • Dr Thomas Bongers, BVH Respiratory Unit • The Librarian, BVH • The Library Staff, Ealing Hospital • Dr Anshul Navalgaria, colleague • Vermeet Kaur, wife • Batch mates.
amytrophic, sclerosis, options, neurostimulating, neuroprotective, multiple, management, lateral, comparison, based, trial
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Dr Pranav Jha (Author), 2017, Neuroprotective vs. Neurostimulating Management Options for Amytrophic Lateral Sclerosis. A Multiple Trial Based Comparison, Munich, GRIN Verlag,


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