131st ENMC International workshop: Selection of Outcome Measures for Peripheral Neuropathy Clinical Trials:

Article Outline

• 1. Introduction
• 2. Advice to the workshop
• 3. Definitions
• 4. Outcome measures at the pathology level
• 5. Outcome measures at the impairment level
  • 5.1. Diabetic neuropathy
  • 5.2. Inflammatory neuropathies
  • 5.3. Hereditary motor and sensory neuropathies
  • 5.4. Painful neuropathies
  • 5.5. Fatigue
• 6. Clinical neurophysiology
  • 6.1. Quantitative sensory testing (QST)
  • 6.2. Composite measures
• 7. Outcome measures at the disability level
• 8. Outcome measures at the handicap and quality of life levels
• 9. Recommendations
• 10. Participants
• Acknowledgements
• References
• Copyright

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1. Introduction 

Besides for diabetic neuropathies, there is currently no consensus regarding the use of outcome measures in peripheral neuropathies. It is, therefore, not surprising that an overwhelming assortment of scales have been applied in therapeutic trials in various forms of peripheral neuropathies. Some scales were introduced before they had been fully clinimetrically tested [1], [2]. Others consisted of a mixture of different clinical modalities. Flawed measures may threaten the validity of trials that use them and impede comparison of results.

With an increasing demand for accuracy, selected outcome measures need to be clinimetrically well evaluated meeting the demands of being simple, valid, reliable, and responsive [1], [2]. Moreover, outcome measures should be unambiguously constructed to represent only one of the outcome levels according to the international classification of functioning, disability and health (the renewed edition of the international classification of impairments, disabilities, and handicaps) [3], [4]. A Medline search revealed 19 published workshops on peripheral neuropathy of which only two addressed the need to obtain consensus on outcome measures [5], [6]. To improve treatments and new drug studies in peripheral neuropathies, consensus regarding the use of a core set of outcome measures for the various peripheral neuropathy forms is urgently needed.

A total of 23 researchers (15 neurologists, one rheumatologist, two neurophysiologists, one patient representative of the Guillain-Barré Syndrome Foundation International, and four pharmaceutical industry-based scientists) from France, Italy, The Netherlands, United Kingdom, and United States of America assembled in Naarden, The Netherlands, to consider the most appropriate outcome measures for trials of treatment in peripheral neuropathy. The group sought to identify available outcome measures for different types of peripheral neuropathy at each level of outcome, ‘pathology’, especially of skin biopsies, ‘symptoms including pain and fatigue', other ‘impairments’ including neurological deficit and electrophysiological measures, ‘disability’, ‘handicap’, and ‘quality of life’ [4], [7].

A Medline search was conducted for the last two decades focusing on outcome measures applied in clinical trials that included patients with a peripheral neuropathy. Reports published in English were identified using the keywords: trial, Guillain-Barré syndrome, GBS, acute (chronic) inflammatory demyelinating (poly)(radiculo)neuropathy, AIDP, CIDP, polyneuritis, painful neuropathy, dysimmune neuropathy, monoclonal gammopathy of undetermined significance neuropathy, MGUS, Charcot-Marie-Tooth neuropathy, CMT, hereditary motor sensory neuropathy, HMSN. Experts in diabetic neuropathy provided additional information regarding potential outcome measures. The applied outcome measures in these studies were categorised according to the international guidelines [4], [7]. The reported scientific soundness (simplicity, validity, reliability, and responsiveness) of identified outcome measures was also considered [1], [2]. Finally, an attempt was made to reach consensus on the most appropriate measures for use in clinical trials in conditions of interest to the European neuromuscular centre (ENMC) such as inflammatory neuropathies, painful neuropathies, and hereditary neuropathy. Diabetic neuropathy was used for comparison since it has been the subject of more work on outcome measures.

In advance of the workshop, a list of outcome measures applied in treatment trials was prepared including their scientific soundness, WHO and quality of life classification [1], [2], [4], [7].

Most participants took part in pre-workshop subgroups and prepared pre-workshop papers focused on controversial areas as a common background for discussion at the workshop.

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2. Advice to the workshop 

At the beginning of the workshop, Maarten Boers, a rheumatologist and co-founder of the Omeract (Outcome Measures in Rheumatology Clinical Trials (www.omeract.org)) group described the way in which the Omeract had achieved and maintained consensus on rheumatoid arthritis outcome measures in the last decade [8], [9]. He introduced the Omeract Filter to test applicability of a measure in a setting: such a measure should be truthful (measure what it's supposed to), discriminate between situations of interest, and feasible in the chosen setting [9]. To come to consensus over a core set of outcome measures and response criteria in various rheumatologic conditions, Omeract has been successful by adopting a data driven approach. He recommended striving for a general accepted view leaving room for ‘political’ considerations. The Omeract filter and process have been instrumental in educating researchers about the clinimetrical requirements of measurement scales.

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3. Definitions 

Richard Hughes introduced a discussion of the international classification of impairments, disabilities, and handicaps and its somewhat more complex renewed version [3], [4]. The quality of life concept as an alternative outcome level from patients' perspectives was addressed [7]. Definitions of these outcome domains are presented in Table 1. The workshop preferred the traditional definitions of impairments, disabilities, and handicaps postulated in the 1980 classification [4]. Ingemar Merkies discussed the ‘clinimetrics’ of these outcome measures and provided definitions for its various entities [1], [2], [10], [11]. He stated that a useful outcome measure should be simple, valid, reliable, and responsive to changes over time and should unambiguously represent one of the WHO outcome domains or quality of life concept. In addition, it was argued that performance criteria such as standardization of test instruments, use of adequately chosen nerve test results corrected for biographic and anthropomorphic variables, and adequate record keeping should also be emphasized when evaluating the clinical applicability of outcome measures.

Table 1. Definition of outcome domains according to the international guidelines [3], [4], [7]

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4. Outcome measures at the pathology level 

In the last decade, skin biopsy for quantification of intraepidermal nerve fibre (IENF) density proved to be a valid and reliable technique to detect the predominant, or even selective, degeneration of small diameter nerve fibres [12], [13], [14], [15], [16], [17]. Skin biopsy is minimally invasive and repeatable. Giuseppe Lauria and Justin McArthur presented the various techniques for evaluating skin biopsies. In particular, differences between light and confocal microscopy were discussed. Standardization of quantification methods and normative data taking anthropometrical information into account were presented and discussed. Furthermore, they stated that the site for biopsy depends on the aim of the study. A correlation between early skin nerve changes and clinical progression of neuropathies and IgM deposits on skin nerves in neuropathy with anti-myelin-associated-glycoprotein antibodies was presented, an example of the prognostic value of biopsies [16], [18]. Models to assess regeneration were also considered. Painful neuropathies were considered the most appropriate illnesses for performing skin biopsies. In painful neuropathies an association has been discovered between skin biopsy findings and clinical outcome measures in the form of both the uni-dimensional visual analogue (VAS) scale and the 11-point-pain intensity numerical scale (PI-NRS) [19], [20]. The gold standard for ‘polyneuropathy’ was questioned; should the diagnosis polyneuropathy be based on clinical grounds or pathological findings such as neurophysiological or skin biopsy findings? Participants agreed that the diagnosis ‘polyneuropathy’ should be primarily based on clinical aspects. For multi-centre studies it was suggested to use a central skin biopsy laboratory. The use of skin biopsies in a more preventitive setting was also suggested, such as in patients with impaired glucose tolerance [15]. Overall, IENF quantification was considered a possible additional outcome measure for both axonal and demyelinating peripheral neuropathies.

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5. Outcome measures at the impairment level 

5.1. Diabetic neuropathy 

Eva Feldman presented a historical review of outcome measures meetings in diabetic neuropathies, that started with the San Antonio consensus conference at which the use was recommended of the neurological impairment scale (NIS), neurophysiological studies, quantitative sensory testing (QST), and autonomic dysfunction studies as primary assessments for diabetic neuropathies [6], [21], [22], [23], [24]. A further development was the use of the NIS with other tests, the NIS-LL+7 score [22]. This composite score grades muscle weakness, reflexes, touch-pressure, joint position sense, vibration, and pin prick in the great toe. It also includes five attributes of nerve conduction velocity in the lower limb, vibration detection threshold as determined by the CASE IV quantitative sensory testing device, and an assessment of variability of the heartbeat to deep breathing. The FDA approved the use of NIS-LL, neurophysiological studies, and QST for clinical trials in diabetic neuropathies. Composite measures were also highlighted including the Michigan Neuropathy Screenings Instrument and the Michigan Diabetic Neuropathy Score, which includes a quantitative neurological examination coupled with nerve conduction studies [25]. The Total Neuropathy Score (TNS) of Cornblath and associates was addressed as a possible composite measure for assessing outcome in diabetic neuropathies [26]. All proposed measures have demonstrated their validity, reliability, and sensitivity to changes over time.

The quantification of impairments should be related to stage of disease. The choice of an outcome measure will depend on the specific questions being asked in a particular study (e.g. trial evaluating the efficacy or safety of a new therapeutic drug versus epidemiological follow-up study). Questions were raised on the responsiveness of symptom-constructed scales. It was considered that these scores, although rather unresponsive, should be included.

5.2. Inflammatory neuropathies 

Eduardo Nobile-Orazio elaborated on the various impairment items that could be investigated in immune-mediated neuropathies. In the symmetrical neuropathy forms, as in Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), various motor outcome measures have been devised for the assessment of strength and were mainly based on the medical research council (MRC) grading system [27]. The most widely used motor outcome measure is the MRC sum score described by Kleyweg and associates and the motor subset of the NIS [23], [24], [28]. These two measures have demonstrated their scientific soundness and are proposed for these neuropathy forms. In multifocal motor neuropathies (MMN), no outcome measures have been systematically evaluated in terms of being valid, reliable, and responsive. Moreover, since MMN has an asymmetrical clinical pattern, an alternative motor sum score was proposed covering ten predefined pairs of muscles that included six most affected muscles. The Vigorimeter was suggested for grip strength assessment in GBS, CIDP, and MMN [29], [30].

Sensory deficit has been assessed in these conditions with different sensory rating scales that included various sensation modalities mediated by different sensory fibres. With the exception of the sensory subset of the NIS and the inflammatory neuropathy cause and treatment (INCAT) sensory sum score, none of the sensory scales has been submitted to a comprehensive clinimetric evaluation in GBS and CIDP [1], [2], [23], [24], [31]. Both measures were considered appropriate. Additional measures may be needed to score cranial nerve (NIS subset), autonomic, and respiratory dysfunction. Reflexes probably do not contribute to disability and need therefore not be measured. Minimum clinically important changes should be addressed, not only from the perspective of the researcher but also from patients' point of view.

In the discussion that followed, the problems in assessing motor deficit in MMN were addressed. Also, the deficit of the MRC sum score being non-linear was highlighted. Suggestions were made for the use of a more linear or exponential outcome measure such as the NIS motor subset, although it was stated that the linear pattern of this measure was also arbitrarily defined.

The INCAT sensory sum score requires assessment of pinprick and vibration sensation in the upper and lower limbs and of two-point discrimination of the index finger. Proximal assessment of sensory deficit is also examined, thereby capturing an anatomical severity gradient of sensory deficit. Vibration sense can be assessed using the graduated Rydel-Seiffer tuning fork and its reported normative data [32], [33]. However, the INCAT sensory sum score does not include light touch or joint position sensation and a scale that included these items would probably be more comprehensive and responsive. In contrast, the NIS sensory subset assesses cotton wool (tactile), pinprick, vibration (a standard tuning fork), and joint position and motion at the dorsum of the index fingers and great toes near the base of the nails. The NIS sensory subset assesses more qualities but omits proximal sensory deficit [23], [24].

5.3. Hereditary motor and sensory neuropathies 

Mary Reilly addressed the problems of assessing change in charcot-marie-tooth (CMT) neuropathies. First, she stated that the natural history of CMT is not known. There are however, indications for a very slow progression pattern of CMT, which introduces a problem regarding the responsiveness of outcome measures. Also, she stated that till recently, no specific measures and outcome studies had previously been developed for these illnesses. The CMT neuropathy score (CMT–NS) was presented and various aspects of its composition were discussed [34]. The validity and reliability of CMT–NS are obtained by demonstrating its correlation with the TNS and NIS [23], [24], [26], [34].

The disadvantages of a composite score such as the CMT-NS were discussed. However, since no other outcome measure studies have been performed in these conditions, the CMT-NS was proposed to assess outcome at the impairment level in these conditions.

5.4. Painful neuropathies 

David Cornblath endorsed the use of uni-dimensional scales in painful neuropathies. In particular, the visual analogue scale (VAS) and the 11-point pain Likert scale were suggested as primary outcome measures in pain-treatment studies [19], [20]. Various aspects like the ‘constancy’ of pain, its intensity, and the time of its assessment were addressed. These aspects should be taken into consideration when pain is being assessed. It was also emphasized that the modality of presentation of scales might affect the outcome; an example is given as a difference in outcome between diary versus electronic assessment of pain.

5.5. Fatigue 

Fatigue is a subjective experience that is categorised by the WHO as an impairment entity [3], [4]. Pieter van Doorn compared uni- to multidimensional fatigue outcome measures. More than 30 fatigue scales are available and have been used in various illnesses [35]. The Fatigue severity scale (FSS) has been most widely used and demonstrated good scientific soundness in various immune-mediated neuropathies [36]. Its use as a secondary outcome measure is proposed. The Fatigue impact scale (FIS) is currently being examined in GBS and CIDP [37]. The possible correlation between fatigue and electrophysiological findings (particularly conduction reduction) was discussed. Other aspects of fatigue like repetitive stimulation that might lead to fatigue, and central versus peripheral located fatigue were briefly addressed.

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6. Clinical neurophysiology 

Joe Arezzo focused on diabetic symmetric distal neuropathy. He stated that electrophysiology is a valid and reliable objective tool in these conditions, and helps in excluding differential diagnoses. Standard procedures were subsequently discussed including common versus uncommon techniques. In diabetic symmetrical distal neuropathy, maximal motor nerve conduction velocity decreases by approximately 0.5m/s per year and amplitude by approximately 5% per year. Electrophysiology should be considered as an endpoint based on its ability to demonstrate deterioration as well as improvement (suggesting the measurement of particularly sural amplitude, peroneal conduction velocity, minimal f-wave latency). If composite electrophysiologic measures are utilized, they should include the assessment of velocity and amplitude in both sensory and motor nerves and, for select nerves, measures sensitive to conduction in both distal and proximal segments. Arezzo stated that electrophysiology is limited since it does not measure small fibres. Luca Padua presented the intradermal reaction at sub-maximum sensory stimulation, suggesting a relation with epidermal end-fibre distribution [38]. Some proposed that assessment of peroneal velocity was particularly valuable, since it demonstrated less variability compared to its amplitude.

Didier Cros presented the electrophysiological patterns of acute and chronic inflammatory demyelinating polyradiculoneuropathies. Electrophysiological difficulties and uncertainties were discussed, such as the need for proximal studies and use of f-waves, the significance for unobtainable sensory nerves action potentials, low amplitude compound muscle action potentials, and decreased recruitment pattern with normal motor unit potentials. Axonal degeneration is also difficult to quantify, occurring in 60% of these patients. Regarding conduction block there are differences between single and multiple stimuli. Single stimuli might overlook ‘frequency dependent conduction block’. There might be a correlation between multiple stimuli detected conduction blocks and fatigue. Difficulties in choosing a definite neurophysiological outcome measure were also addressed, since demyelinating and axonal degeneration may overlap. A review of electrophysiological outcome measures in published trials for CIDP, over the last two decades, was presented and showed a wide heterogeneity of used parameters. The more used electrophysiological outcome measures were motor nerve conduction velocities and amplitude of the motor evoked potentials, followed by distal motor latencies, and F-latencies. Only the first 2 electrophysiological outcome measures showed significant improvement in more than 1 trial. For the future, conduction blocks and sensory potentials should be considered. In CMT type I and II, motor unit number estimation and testing proximal nerves were suggested as possibly useful.

6.1. Quantitative sensory testing (QST) 

Peter Dyck questioned the reproducibility of standard scales and stated that standardization of outcome measures was much more important. QST was suggested as a valuable primary outcome measure especially in sensory neuropathies, since it captures the relevant impairment in a standardized manner [39]. Researchers should bear in mind that aspects like age, sex, and race affect all tests. Hence, scores obtained from outcome measures should be controlled and corrected for confounders like these, as has been done for QST.

In the discussion that followed, QST could probably be used as a screening tool for diabetic neuropathy. The clinically minimum important difference is proposed as ‘the least amount of difference a neurologist can recognize at examination’, e.g. 2 points on NIS. Others disagreed and proposed another approach like reversing of a certain amount of progression. QST as a primary endpoint in neuropathy trials was questioned, since impairments do not necessarily lead to disability or deficit in quality of life.

6.2. Composite measures 

David Cornblath stated that composite measures provide a more holistic approach to an illness, are less time consuming, and are readily available. However, a change in score using a composite measure cannot be assigned to one particular level of dysfunction. Not all entities incorporated in composite measures are clinically relevant. Composite measures may mix impairments, disability, handicap, and quality of life entities depending on the choice made. Some felt that these features reduced the acceptability of composite measures. Others disagreed and emphasized that such scores may better represent all features of the illness and be more sensitive to change.

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7. Outcome measures at the disability level 

Richard Hughes discussed disability measures, including the GBS-disability score, Rankin scale, and the INCAT overall disability sum score (ODSS) [40], [41], [42]. The advantages of the ODSS compared to the other measures were highlighted. The ODSS has more steps in the ambulation part and also includes deficit in the upper extremities. The ODSS was recently examined in these conditions for its scientific soundness and demonstrated a good correlation with impairment measures and with patients' own judgment of their clinical state [42], [43], [44]. The ODSS was therefore proposed as the disability endpoint in GBS and CIDP clinical trials.

It was debated whether the ODSS could be used in MMN trials. In a current trial in MMN (van den Berg L, personal communication) the ODSS demonstrated leg dysfunction in one third of patients.

Marinus Vermeulen presented the new AMC Linear Disability Scale (ALDS) [45]. Reasons for its development were provided. A total of 100 items were selected out of 190 items that were initially recruited from 110 disability measures. These items were examined in more than 4000 patients with chronic illnesses, thereby estimating item difficulties (item weights). Its scientific soundness was also demonstrated. The ALDS had less floor and ceiling effects and provided comparable data between various chronic illnesses due to its linear setting of patients' abilities and item-weights than other scales [45]. ALDS and ODSS findings were compared in 15 patients with CIDP being treated with pulsed high dose dexamethasone. In contrast to the ODSS, which demonstrated ceiling effect in these patients, the ALDS was still responsive to change (van Schaik I personal communication). The ALDS needs to be clinimetrically tested in other countries and languages. Since, more units in a scale would most probably lead to a higher responsive, it was questioned whether the responsiveness of the ALDS would reflect clinical important difference. Also, regarding choosing the primary endpoint for randomised clinical trials in peripheral neuropathies, some participants favoured measures of impairments with disability scales as secondary endpoints, while others preferred disability measures as primary endpoint over impairment scales.

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8. Outcome measures at the handicap and quality of life levels 

Marinus Vermeulen questioned whether we should measure handicap. Impairment measures test whether or not a treatment works. Disability measures tell us whether a patient has a personal benefit from therapy. Moreover, impairment is better related to disability and is scarcely reflected in handicap and quality or life [46]. He proposed not to assess handicap, since it simply reflects extended disability and change in impairment is less likely to be associated with a change in handicap [47].

Luca Padua stated that there has been an exponential increase in the use quality of life measurements in clinical trials. They introduce the perspective of the patient into the assessment. Patient oriented assessments are better at telling whether the patient is benefiting from a particular therapy. Additional information could also be recruited when comparing results with normal values for particular outcome measures. Differences between generic and disease specific patient oriented assessments were also provided by Padua. Only two neuropathy specific quality of life instruments have been developed and clinimetrically evaluated [48], [49]. Data in favour of disease specific measures were presented. Health-cost utilities should be introduced in future neuropathy trials. EuroQol as a tool for health economic assessments was mentioned [50]. In diabetic neuropathy, the use of neuropathy- and foot ulcer-specific quality of life instrument was suggested [48].

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9. Recommendations 

Outcome measures should be specific for each neuropathy and intervention.

Selected outcome measures must be feasible, valid, reliable, and responsive [1], [2].

In diseases such as in MMN, outcome measures need to be evaluated covering various domains [1], [2].

Adverse events should always be assessed and reported.

In diseases in which symptoms are prominent, such as painful neuropathy, the use of symptom-based outcome measures should be considered.

For all trials the baseline anthropometric data and disease severity of the patients should be reported.

Evaluators should be trained in the application of the selected instruments before the start of each study.

A minimum core set of outcome measures that covered specific domains for each disease was suggested (Table 2).

Table 2. Minimum core set of outcome measures for clinical trials in peripheral neuropathies

ALDS, AMC linear disability score [45]; Boulton's quality of life measure, Boulton's neuropathy and foot ulcer-specific quality of life measure [48]; CIDP, chronic inflammatory demyelinating polyradiculoneuropathy; CMT, Charcot-Marie-Tooth neuropathies; CMT-NS, Charcot-Marie-Tooth neuropathy score; GBS, Guillain-Barré syndrome; GBS-disability score, f-score [40]; incat sensory sumscore, inflammatory neuropathy cause and treatment sensory sumscore [31]; MMN, multifocal motor neuropathy; MNCV, motor nerve conduction velocity; MRC sumscore, Medical Research Council sumscore [28]; MGUSP, monoclonal gammopathy of undetermined significance related polyneuropathy; NIS(-LL), neuropathy impairment score in the lower limbs [22], [23], [24]; NSP, neuropathy symptoms profile [52]; NSS, neurological symptom score [53]; NTSS, neuropathy total symptom score [54]; ODSS, overall disability sumscore [42]; ODSS?, ODSS could be considered in CMT neuropathies; PI-NRS, 11-point-pain intensity numerical scale [20]; SF-36, medical outcome study short form 36 items health status [51], [55]; TNS, total neuropathy score [26]; VAS, visual analogue scale [19]; Vickrey's quality of life measure, Vickrey's peripheral neuropathy specific quality of life measure [49]; VPT, vibratory perception threshold [21].

Research should be conducted to compare the responsiveness of the scales recommended in different patient populations. In GBS, CIDP, and gammopathy related neuropathies, comparison is needed between MRC sum score versus NIS motor subset and between INCAT sensory sum score versus NIS sensory subset [22], [23], [24], [28], [31].

The ALDS should be tested in a wider range of peripheral neuropathies and in more centres [45].

Assessment of both quality of life with SF-36 and health utility with the EuroQol should be considered [50], [51].

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10. Participants 

Pharmaceutical representatives: Dr G. Parks (Sankyo Pharma Inc., Germany), Dr T. Ho (Merck and Co, Inc., USA), Dr E. Bastyr (Eli Lilly and Company, USA), Dr K. Schäfer (Bayer Vital GmbH, Germany).

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Acknowledgements 

This workshop was made possible thanks to the financial support of the European neuromuscular centre (ENMC) and ENMC main sponsors: association Française contre les Myopathies (France), Deutsche Gesellschaft für Muskelkranke (Germany), Telethon Foundation (Italy), Muscular Dystrophy Campaign (UK), Muskelvindfonden (Denmark), Prinses Beatrix Fonds (The Netherlands), Schweizerische Stiftung für die Erforschung der Muskelkrankheiten (Switzerland), Österreichische Muskelforschung (Austria), Vereniging Spierziekten Nederland (The Netherlands).

The following pharmaceutical industries also contributed financially to this workshop:

Baxter BioScience, Bayer Healthcare LLC, Eli Lilly and Company, Merck and Co., Inc., Mitsubishi Pharma America, Inc., Sankyo Pharma Inc.

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