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    Clinical Trial Results:
    A phase III, multicenter, randomized, parallel groups study to assess the efficacy and safety of 0,5 mg Tizaspray® administered intranasally versus Sirdalud® 2 mg tablets, in patients with acute low back pain

    Summary
    EudraCT number
    		 2014-003040-12
    Trial protocol
    		 IT  
    Global end of trial date
    20 Sep 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Jan 2018
    First version publication date
    24 Jan 2018
    Other versions
    Summary report(s)
    		 TZSA2 - Clinical Trial Summary Report

    Trial information

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    Trial identification
    Sponsor protocol code
    TZSA2
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    MDM S.p.A.
    Sponsor organisation address
    Via Volturno 29/b, Monza, Italy, 20052
    Public contact
    Servizio Segreteria MDM, MDM S.p.A., +39 039 3909110, mdm@mdmspa.com
    Scientific contact
    Servizio Segreteria MDM, MDM S.p.A., +39 039 3909110, mdm@mdmspa.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    20 Sep 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Sep 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Sep 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    1)To evaluate the muscle relaxant activity of Tizaspray 0.5 mg compared to Sirdalud 2 mg tablets as assessed by the “hand-to-floor” distance at baseline, day 3 and day 8.2)To evaluate the efficacy of Tizaspray 0.5 mg for the treatment of acute low back pain compared to Sirdalud 2 mg tablets as assessed by the Low Back Pain Intensity Scale (VAS) over maximum 7 days of treatment. 3)To evaluate the muscle relaxant activity of Tizaspray 0.5 mg compared to Sirdalud 2 mg tablets as assessed by the Schober test (positive/negative) at baseline, day 3 and day 8.
    Protection of trial subjects
    A review of the safety surveillance database revealed cases of intentional and accidental tizanidine overdose. The clinical manifestations of tizanidine overdose were consistent with its known pharmacology. In the majority of cases a decrease in sensorium was observed including lethargy, somnolence, confusion and coma. Depressed cardiac function are also observed including most often bradycardia and hypotension. Respiratory depression is another common feature of tizanidine overdose. Should overdose occur, basic steps to ensure the adequacy of an airway and the monitoring of cardiovascular and respiratory systems should be undertaken. In general, symptoms resolve within one to three days following discontinuation of tizanidine and administration of appropriate therapy. Due to the similar mechanism of action, symptoms and management of tizanidine overdose are to those following clonidine overdose. Patients experiencing somnolence, dizziness or any signs or symptoms of hypotension should refrain from activities requiring a high degree of alertness, e.g. driving a vehicle or operating machines. Caution is advised when Tizanidine is to be used with antihypertensives, including diuretics, since it may occasionally cause hypotension and bradycardia. In some patients rebound hypertension and tachycardia have been observed upon abrupt discontinuation of tizanidine when concomitantly used with antihypertensive drugs. In extreme cases, rebound hypertension might lead to cerebrovascular accident. Alcohol and sedatives may enhance the sedative action of tizanidine. Patients were allowed to use the provided study Paracetamol for “rescue analgesia” for their low back pain. No more than 6 tablets may be taken in a 24 hour period (doses separated by at least 4 hours). The rescue medication was provided by the Sponsor in 500 mg tablets. The patient will be instructed to take tablets, possibly, on full stomach and to take the lowest number of possible tablets.
    Background therapy
    		 Not applicable
    Evidence for comparator
    		 Tizanidine HCl is the active substance of the medicinal product Sirdalud® tablets 2 mg, 4 mg, and 6 mg, marketed worldwide by Novartis Pharma since many years. Tizanidine HCl is a centrally acting skeletal muscle relaxant: it is an α2-adrenergic agonist structurally related to clonidine and acts mainly at spinal and supraspinal levels to inhibit excitatory interneurones. It is used for the symptomatic relief of spasticity associated with multiple scleroses or with spinal cord injury or disease. It is also used in the symptomatic treatment of painful muscle spasm associated with musculoskeletal conditions. The compound has got marketing approval in UK, USA, Canada, Italy, Japan, Belgium, Brazil, Denmark, Egypt, Finland, Germany, and Austria. In Italy the authorised indications are: painful muscle spasms related to static and functional diseases of spine (cervical and lumbar arthrosis syndromes, lumbago, torticollis) or following surgery (disc protusion, coxarthrosis); spasticity associated with neurological disorders (multiple sclerosis, chronic myelopathy, degenerative spinal disorders, stroke, etc.). The physico-chemical properties of tizanidine, the pharmaceutical properties of tablets, the nonclinical pharmacology, toxicology, pharmacokinetics and metabolism and the clinical efficacy, safety, pharmacokinetics and metabolism are well understood.
    Actual start date of recruitment
    08 Apr 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Romania: 168
    Country: Number of subjects enrolled
    Italy: 68
    Worldwide total number of subjects
    236
    EEA total number of subjects
    236
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    234
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients have been recruited between 8-Apr-2015 and 30-Jan-2017 in Italy (5 clinical sites) and Romania (5 clinical sites). The recruitment was competitive and only three clinical sites in Italy and four clinical sites in Romania have recruited some patients.

    Pre-assignment
    Screening details
    		 At Visit 1 (Day 1), prior to performing any trial assessments, the Investigator ensured that the patient had provided written informed consent. When screening procedures were performed, if eligible, the patient was immediately randomized and provided with the study treatment (first dose taken directly at site).

    Period 1
    Period 1 title
    Treatment period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    The two treatments (Tizaspray and Sirdalud) had different formulations (nasal spray and oral tablets, respectively) and a double dummy technique was not applicable. Treatment was assigned as follows: - Once eligibility is established (according to Inclusion/Exclusion Criteria), the Investigator had to enter the Electronic Case Report Form (e-CRF) and randomize the patient via web. The system indicated the kit number and the the type of treatment to assign to the patient.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 TIZASPRAY
    Arm description
    		 Patients treated with Tizaspray® nasal solution
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tizaspray® nasal solution
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nasal spray, solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    8.169 mg/ml of tizanidine hydrochloride corresponding to 0.5 mg of tizanidine base/70 µL puff. 3 x 1 puff daily, intranasal administration.

    Arm title
    		 SIRDALUD
    Arm description
    		 Patients treated with Sirdalud® 2mg oral tablets
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Sirdalud® 2mg oral tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2,29 mg/tablet of tizanidine hydrochloride corresponding to 2.0 mg of tizanidine base. 3 x 1 tablet daily, oral route.

    Number of subjects in period 1
    		TIZASPRAY SIRDALUD
    Started
    119
    117
    Completed
    114
    113
    Not completed
    5
    4
         Consent withdrawn by subject
    4
    1
         Adverse event, non-fatal
    -
    2
         Lost to follow-up
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    TIZASPRAY
    Reporting group description
    		 Patients treated with Tizaspray® nasal solution

    Reporting group title
    SIRDALUD
    Reporting group description
    		 Patients treated with Sirdalud® 2mg oral tablets

    Reporting group values
    		 TIZASPRAY SIRDALUD Total
    Number of subjects
    		 119 117 236
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 119 115 234
        From 65-84 years
    		 0 2 2
    Gender categorical
    Units: Subjects
        Female
    		 66 67 133
        Male
    		 53 50 103
    Subject analysis sets

    Subject analysis set title
    Safety population Tizaspray
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Randomized patients taking at least one dose of Tizaspray

    Subject analysis set title
    Safety population Sirdalud
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Randomized patients taking at least one dose of Sirdalud

    Subject analysis set title
    ITT population Tizaspray
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Patients randomly assigned to the Tizaspray group receiving at least one treatment dose and having at least one post-randomization assessment

    Subject analysis set title
    ITT population Sirdalud
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Patients randomly assigned to the Sirdalud group receiving at least one treatment dose and having at least one post-randomization assessment

    Subject analysis set title
    PP population Tizaspray
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients randomized in the Tizaspray group with treatment compliance between 80%-130% inclusive, that had all post-randomization efficacy assessments and performed Visit 3 within the planned window (Day 8+2)

    Subject analysis set title
    PP population Sirdalud
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients randomized in the Sirdalud group with treatment compliance between 80%-130% inclusive, that had all post-randomization efficacy assessments and performed Visit 3 within the planned window (Day 8+2)

    Subject analysis sets values
    		 Safety population Tizaspray Safety population Sirdalud ITT population Tizaspray ITT population Sirdalud PP population Tizaspray PP population Sirdalud
    Number of subjects
    118
    116
    115
    115
    99
    106
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    118
    115
    115
    114
    99
    106
        From 65-84 years
    0
    1
    0
    1
    0
    0
    Age continuous
    Units:
        
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    65
    67
    63
    67
    53
    62
        Male
    53
    49
    52
    48
    46
    44

    End points

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    End points reporting groups
    Reporting group title
    TIZASPRAY
    Reporting group description
    		 Patients treated with Tizaspray® nasal solution

    Reporting group title
    SIRDALUD
    Reporting group description
    		 Patients treated with Sirdalud® 2mg oral tablets

    Subject analysis set title
    Safety population Tizaspray
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Randomized patients taking at least one dose of Tizaspray

    Subject analysis set title
    Safety population Sirdalud
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Randomized patients taking at least one dose of Sirdalud

    Subject analysis set title
    ITT population Tizaspray
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Patients randomly assigned to the Tizaspray group receiving at least one treatment dose and having at least one post-randomization assessment

    Subject analysis set title
    ITT population Sirdalud
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Patients randomly assigned to the Sirdalud group receiving at least one treatment dose and having at least one post-randomization assessment

    Subject analysis set title
    PP population Tizaspray
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients randomized in the Tizaspray group with treatment compliance between 80%-130% inclusive, that had all post-randomization efficacy assessments and performed Visit 3 within the planned window (Day 8+2)

    Subject analysis set title
    PP population Sirdalud
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients randomized in the Sirdalud group with treatment compliance between 80%-130% inclusive, that had all post-randomization efficacy assessments and performed Visit 3 within the planned window (Day 8+2)

    Primary: Changes in Hand-to-floor distance

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    End point title
    		 Changes in Hand-to-floor distance
    End point description
    The changes in Hand-to-floor distance between Day 1 (baseline) and Day 8 (end of treatment) have been compared between treatment groups
    End point type
    Primary
    End point timeframe
    Between Day 1 and Day 8
    End point values
    		 TIZASPRAY SIRDALUD ITT population Tizaspray ITT population Sirdalud PP population Tizaspray PP population Sirdalud
    Number of subjects analysed
    114
    114
    114
    114
    99
    106
    Units: cm
        arithmetic mean (standard deviation)
    -15.51 ( 13.16 )
    -11.51 ( 12.64 )
    -15.51 ( 13.16 )
    -11.51 ( 12.64 )
    -14.40 ( 11.33 )
    -10.95 ( 11.91 )
    Attachments
    		 Hand-to-floor - Differences from baseline (ITT)
    Statistical analysis title
    		 T-test on Hand-to-Floor Distance (ITT)
    Statistical analysis description
    T-test on changes between Day 1 and Day 8 in Hand-to-Floor Distance (ITT)
    Comparison groups
    ITT population Tizaspray v ITT population Sirdalud
    Number of subjects included in analysis
    228
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0201 [1]
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.37
         upper limit
    		 -0.63
    Notes
    [1] - The difference between treatment groups was statistically significant at p<0.05
    Statistical analysis title
    		 ANCOVA on Hand-to-Floor Distance (ITT)
    Statistical analysis description
    ANCOVA on changes between Day 1 and Day 8 in Hand-to-Floor Distance (ITT), with factors for treatment, site and baseline values
    Comparison groups
    ITT population Tizaspray v ITT population Sirdalud
    Number of subjects included in analysis
    228
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0009 [2]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.21
         upper limit
    		 -1.62
    Notes
    [2] - The difference between treatment groups was statistically significant at p<0.001
    Statistical analysis title
    		 T-test on Hand-to-Floor Distance (PP)
    Statistical analysis description
    T-test on changes between Day 1 and Day 8 in Hand-to-Floor Distance (PP)
    Comparison groups
    PP population Sirdalud v PP population Tizaspray
    Number of subjects included in analysis
    205
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0347 [3]
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.66
         upper limit
    		 -0.25
    Notes
    [3] - The difference between treatment groups was statistically significant at p<0.05
    Statistical analysis title
    		 ANCOVA on Hand-to-Floor Distance (PP)
    Statistical analysis description
    ANCOVA on changes between Day 1 and Day 8 in Hand-to-Floor Distance (PP), with factors for treatment, site and baseline values
    Comparison groups
    PP population Tizaspray v PP population Sirdalud
    Number of subjects included in analysis
    205
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0002 [4]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -4.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.47
         upper limit
    		 -2.03
    Notes
    [4] - The difference between treatment groups was statistically significant at p<0.001

    Primary: Changes in Average Low Back Pain (VAS)

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    End point title
    		 Changes in Average Low Back Pain (VAS)
    End point description
    End point type
    Primary
    End point timeframe
    Between Day 1 and Day 8
    End point values
    		 TIZASPRAY SIRDALUD ITT population Tizaspray ITT population Sirdalud PP population Tizaspray PP population Sirdalud
    Number of subjects analysed
    114
    114
    114
    114
    99
    106
    Units: mm
        arithmetic mean (standard deviation)
    -44.96 ( 18.38 )
    -35.70 ( 20.81 )
    -44.96 ( 18.38 )
    -35.70 ( 20.81 )
    -43.93 ( 17.44 )
    -35.19 ( 20.52 )
    Attachments
    		 Low back pain - Differences from baseline (ITT)
    Statistical analysis title
    		 T-test on Low back pain (ITT)
    Statistical analysis description
    T-test on changes in low back pain between Day 1 and Day 8 (ITT population)
    Comparison groups
    ITT population Tizaspray v ITT population Sirdalud
    Number of subjects included in analysis
    228
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0004 [5]
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -9.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.39
         upper limit
    		 -4.14
    Notes
    [5] - The difference between treatment groups was statistically significant at p<0.001
    Statistical analysis title
    		 ANCOVA on Low back pain (ITT)
    Statistical analysis description
    ANCOVA on changes in low back pain between Day 1 and Day 8 (ITT population), with factors for treatment, site and baseline values
    Comparison groups
    ITT population Tizaspray v ITT population Sirdalud
    Number of subjects included in analysis
    228
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [6]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -8.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.14
         upper limit
    		 -4.7
    Notes
    [6] - The difference between treatment groups was statistically significant at p<0.001
    Statistical analysis title
    		 T-test on Low back pain (PP)
    Statistical analysis description
    T-test on changes in low back pain between Day 1 and Day 8 (PP population)
    Comparison groups
    PP population Tizaspray v PP population Sirdalud
    Number of subjects included in analysis
    205
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0012 [7]
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -8.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.01
         upper limit
    		 -3.49
    Notes
    [7] - The difference between treatment groups was statistically significant at p<0.01
    Statistical analysis title
    		 ANCOVA on Low back pain (PP)
    Statistical analysis description
    ANCOVA on changes in low back pain between Day 1 and Day 8 (PP population), with factors for treatment, site and baseline values
    Comparison groups
    PP population Tizaspray v PP population Sirdalud
    Number of subjects included in analysis
    205
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [8]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -9.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.92
         upper limit
    		 -5.59
    Notes
    [8] - The difference between treatment groups was statistically significant at p<0.001

    Primary: Positivity to Schober's test

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    End point title
    		 Positivity to Schober's test
    End point description
    Patients with Schober's test higher than 5 mm were classified as positive, patients with higher Schober's test results were classified as negative. The number of patients with positive Schober's test was compared between treatment groups.
    End point type
    Primary
    End point timeframe
    At Day 8 (+2)
    End point values
    		 TIZASPRAY SIRDALUD ITT population Tizaspray ITT population Sirdalud PP population Tizaspray PP population Sirdalud
    Number of subjects analysed
    114
    114
    114
    114
    99
    106
    Units: Patients positive to Schober's test
    30
    46
    30
    46
    23
    41
    Statistical analysis title
    		 Chi-square test on Schober's test positivity (ITT)
    Statistical analysis description
    Chi-square test to assess the difference between treatment groups in the proportion of patients positive to Schober's test at Day 8 (ITT population)
    Comparison groups
    ITT population Tizaspray v ITT population Sirdalud
    Number of subjects included in analysis
    228
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0246 [9]
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [9] - The difference between treatment groups was statistically significant at p<0.05
    Statistical analysis title
    		 Logistic regression on Schober's test (ITT)
    Statistical analysis description
    Logistic regression to estimate OR (adjusted for site) between treatment groups for the proportion of patients positive to Schober's test at Day 8 (ITT population).
    Comparison groups
    ITT population Tizaspray v ITT population Sirdalud
    Number of subjects included in analysis
    228
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.005 [10]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.17
         upper limit
    		 0.73
    Notes
    [10] - The difference between treatment groups was statistically significant at p<0.01
    Statistical analysis title
    		 Chi-square test on Schober's test positivity (PP)
    Statistical analysis description
    Chi-square test to assess the difference between treatment groups in the proportion of patients positive to Schober's test at Day 8 PP population)
    Comparison groups
    PP population Tizaspray v PP population Sirdalud
    Number of subjects included in analysis
    205
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0171 [11]
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [11] - The difference between treatment groups was statistically significant at p<0.05
    Statistical analysis title
    		 Logistic regression on Schober's test (PP)
    Statistical analysis description
    Logistic regression to estimate OR (adjusted for site) between treatment groups for the proportion of patients positive to Schober's test at Day 8 (PP population)
    Comparison groups
    PP population Tizaspray v PP population Sirdalud
    Number of subjects included in analysis
    205
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0064 [12]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.14
         upper limit
    		 0.73
    Notes
    [12] - The difference between treatment groups was statistically significant at p<0.01

    Primary: Changes in Low Back Pain on movement by day

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    End point title
    		 Changes in Low Back Pain on movement by day
    End point description
    Low back Pain on movement was assessed daily by patient's questionnaire. The differences between Day 1 and each following day have been estimated and analyzed. The difference between treatment groups was statistically significant since Day 6 (P<0.01). The analysis at Day 7 is reported here.
    End point type
    Primary
    End point timeframe
    Between Day 1 and Day 7
    End point values
    		 TIZASPRAY SIRDALUD ITT population Tizaspray ITT population Sirdalud PP population Tizaspray PP population Sirdalud
    Number of subjects analysed
    112
    110
    112
    110
    98
    105
    Units: mm
        arithmetic mean (standard deviation)
    -40.96 ( 20.65 )
    -33.43 ( 22.82 )
    -40.96 ( 20.65 )
    -33.43 ( 22.82 )
    -41.22 ( 20.37 )
    -33.12 ( 22.45 )
    Attachments
    		 Differences in Low back pain on moving by day(ITT)
    Statistical analysis title
    		 T-Test on Low back pain (ITT)
    Statistical analysis description
    T-test on difference in low back pain between day 1 and day 7 (ITT population)
    Comparison groups
    ITT population Sirdalud v ITT population Tizaspray
    Number of subjects included in analysis
    222
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0106 [13]
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -7.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.28
         upper limit
    		 -1.77
    Notes
    [13] - The difference between treatment groups was statistically significant at p<0.01667
    Statistical analysis title
    		 ANCOVA on Low back pain (ITT)
    Statistical analysis description
    ANCOVA on difference in low back pain between day 1 and day 7, with factors for treatment, site and baseline values (ITT population)
    Comparison groups
    ITT population Tizaspray v ITT population Sirdalud
    Number of subjects included in analysis
    222
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0014 [14]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -7.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.66
         upper limit
    		 -2.85
    Notes
    [14] - The difference between treatment groups was statistically significant at p<0.001
    Statistical analysis title
    		 T-Test on Low back pain (PP)
    Statistical analysis description
    T-test on difference in low back pain between day 1 and day 7 (PP population)
    Comparison groups
    PP population Tizaspray v PP population Sirdalud
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0078 [15]
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -8.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.05
         upper limit
    		 -2.15
    Notes
    [15] - The difference between treatment groups was statistically significant at p<0.01
    Statistical analysis title
    		 ANCOVA on Low back pain (PP)
    Statistical analysis description
    ANCOVA on difference in low back pain between day 1 and day 7, with factors for treatment, site and baseline values (PP population)
    Comparison groups
    PP population Sirdalud v PP population Tizaspray
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0001 [16]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -9.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.74
         upper limit
    		 -4.87
    Notes
    [16] - The difference between treatment groups was statistically significant at p<0.001

    Primary: Changes in Low Back Pain at rest by day

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    End point title
    		 Changes in Low Back Pain at rest by day
    End point description
    Low back Pain at rest was assessed daily by patient's questionnaire. The differences between Day 1 and each following day have been estimated and analyzed. The difference between treatment groups was statistically significant since Day 4 (P<0.05). The analysis at Day 7 is reported here.
    End point type
    Primary
    End point timeframe
    Between day and day 7
    End point values
    		 TIZASPRAY SIRDALUD ITT population Tizaspray ITT population Sirdalud PP population Tizaspray PP population Sirdalud
    Number of subjects analysed
    112
    110
    112
    110
    98
    105
    Units: mm
        arithmetic mean (standard deviation)
    -40.69 ( 19.78 )
    -31.57 ( 21.94 )
    -40.69 ( 19.78 )
    -31.57 ( 21.94 )
    -39.99 ( 19.55 )
    -31.55 ( 21.32 )
    Attachments
    		 Differences in Low back pain at rest by day (ITT)
    Statistical analysis title
    		 T-test on Low back pain (ITT)
    Statistical analysis description
    T-test on low back pain at rest (ITT population)
    Comparison groups
    ITT population Tizaspray v ITT population Sirdalud
    Number of subjects included in analysis
    222
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0013 [17]
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -9.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.64
         upper limit
    		 -3.59
    Notes
    [17] - The difference between treatment groups was statistically significant at p<0.01
    Statistical analysis title
    		 ANCOVA on Low back pain (ITT)
    Statistical analysis description
    ANCOVA on low back pain at rest (ITT population), with factors for treatment, site and baseline values
    Comparison groups
    ITT population Tizaspray v ITT population Sirdalud
    Number of subjects included in analysis
    222
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0005 [18]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -7.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.12
         upper limit
    		 -3.4
    Notes
    [18] - The difference between treatment groups was statistically significant at p<0.001
    Statistical analysis title
    		 T-test on Low back pain (PP)
    Statistical analysis description
    T-test on low back pain at rest (PPpopulation)
    Comparison groups
    PP population Tizaspray v PP population Sirdalud
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0037 [19]
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -8.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.11
         upper limit
    		 -2.76
    Notes
    [19] - The difference between treatment groups was statistically significant at p<0.01
    Statistical analysis title
    		 ANCOVA on Low back pain (PP)
    Statistical analysis description
    ANCOVA on low back pain at rest (PP population), with factors for treatment, site and baseline values
    Comparison groups
    PP population Tizaspray v PP population Sirdalud
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0001 [20]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -9.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.43
         upper limit
    		 -4.59
    Notes
    [20] - The difference between treatment groups was statistically significant at p<0.001

    Primary: Changes in Low Back Pain when sleeping

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    End point title
    		 Changes in Low Back Pain when sleeping
    End point description
    Low back Pain when sleeping was assessed daily by patient's questionnaire. The differences between Day 1 and each following day have been estimated and analyzed. The difference between treatment groups was statistically significant since Day 6 (P<0.01667). The analysis at Day 7 is reported here.
    End point type
    Primary
    End point timeframe
    Between day 1 and day 7
    End point values
    		 TIZASPRAY SIRDALUD ITT population Tizaspray ITT population Sirdalud PP population Tizaspray PP population Sirdalud
    Number of subjects analysed
    112
    111
    112
    111
    99
    105
    Units: mm
        arithmetic mean (standard deviation)
    -37.14 ( 22.65 )
    -30.64 ( 20.74 )
    -37.14 ( 22.65 )
    -30.64 ( 20.74 )
    -38.04 ( 22.36 )
    -29.77 ( 19.39 )
    Attachments
    		 Differences in Low back pain on sleep by day(ITT)
    Statistical analysis title
    		 T-test on Low back pain (ITT)
    Statistical analysis description
    T-test on Low back pain (ITT population)
    Comparison groups
    ITT population Tizaspray v ITT population Sirdalud
    Number of subjects included in analysis
    223
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0264 [21]
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -6.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.24
         upper limit
    		 -0.77
    Notes
    [21] - The difference between treatment groups was statistically significant at p<0.05
    Statistical analysis title
    		 ANCOVA on Low back pain (ITT)
    Statistical analysis description
    ANCOVA on Low back pain (ITT population), with factors for treatment, site and baseline values
    Comparison groups
    ITT population Tizaspray v ITT population Sirdalud
    Number of subjects included in analysis
    223
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0007 [22]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -7.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.58
         upper limit
    		 -3.41
    Notes
    [22] - The difference between treatment groups was statistically significant at p<0.001
    Statistical analysis title
    		 T-test on Low back pain (PP)
    Statistical analysis description
    T-test on Low back pain (PP population)
    Comparison groups
    PP population Tizaspray v PP population Sirdalud
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0052 [23]
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -8.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.04
         upper limit
    		 -2.5
    Notes
    [23] - The difference between treatment groups was statistically significant at p<0.01
    Statistical analysis title
    		 ANCOVA on Low back pain (PP)
    Statistical analysis description
    ANCOVA on Low back pain (PP population), with factors for treatment, site and baseline values
    Comparison groups
    PP population Tizaspray v PP population Sirdalud
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [24]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -9.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.16
         upper limit
    		 -5.16
    Notes
    [24] - The difference between treatment groups was statistically significant at p<0.001

    Secondary: Changes in Low Back Pain after 2nd dose (Day 1)

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    End point title
    		 Changes in Low Back Pain after 2nd dose (Day 1)
    End point description
    Low back Pain was assessed after the second administration by patient's questionnaire. Low back pain was assessed at the moment of the second dose and after 30, 60, 90, 180 minutes. The differences between the moment of the second dose and after 30, 60, 90, 180 minutes have been estimated and analyzed. The difference between treatment groups was statistically significant after 30 and 60 minutes (p < 0.01), then the differences lowered. The analysis at 60 minutes is reported here.
    End point type
    Secondary
    End point timeframe
    On day 1
    End point values
    		 TIZASPRAY SIRDALUD ITT population Tizaspray ITT population Sirdalud PP population Tizaspray PP population Sirdalud
    Number of subjects analysed
    109
    106
    109
    106
    95
    100
    Units: mm
        arithmetic mean (standard deviation)
    -10.73 ( 11.72 )
    -7.16 ( 7.20 )
    -10.73 ( 11.72 )
    -7.16 ( 7.20 )
    -11.00 ( 11.37 )
    -7.19 ( 7.33 )
    Attachments
    		 Low back pain after 2nd dose (Day 1)
    Statistical analysis title
    		 T-test on Low back pain (ITT)
    Statistical analysis description
    T-test on Low back pain after second administration (ITT population)
    Comparison groups
    ITT population Tizaspray v ITT population Sirdalud
    Number of subjects included in analysis
    215
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [25]
    P-value
    		 = 0.0078
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.2
         upper limit
    		 -0.95
    Notes
    [25] - The difference between treatment groups was statistically significant at p<0.01
    Statistical analysis title
    		 ANCOVA on Low back pain (ITT)
    Statistical analysis description
    ANCOVA on Low back pain after second administration (ITT population), with factors for treatment, site and baseline values
    Comparison groups
    ITT population Tizaspray v ITT population Sirdalud
    Number of subjects included in analysis
    215
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0117 [26]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.53
         upper limit
    		 -0.7
    Notes
    [26] - The difference between treatment groups was statistically significant at p<0.01667
    Statistical analysis title
    		 T-test on Low back pain (PP)
    Statistical analysis description
    T-test on Low back pain after second administration (PP population)
    Comparison groups
    PP population Tizaspray v PP population Sirdalud
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0057 [27]
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.5
         upper limit
    		 -1.12
    Notes
    [27] - The difference between treatment groups was statistically significant at p<0.01
    Statistical analysis title
    		 ANCOVA on Low back pain (PP)
    Statistical analysis description
    ANCOVA on Low back pain after second administration (PP population), with factors for treatment, site and baseline values
    Comparison groups
    PP population Tizaspray v PP population Sirdalud
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0085 [28]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.86
         upper limit
    		 -0.87
    Notes
    [28] - The difference between treatment groups was statistically significant at p<0.01

    Secondary: Changes in Low Back Pain after 2nd dose (Day 2)

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    End point title
    		 Changes in Low Back Pain after 2nd dose (Day 2)
    End point description
    The differences between the moment of the second dose and after 30, 60, 90, 180 minutes have been estimated and analyzed. The difference between treatment groups was statistically significant after 30 and 60 minutes (p < 0.01), then the differences lowered. The analysis at 60 minutes is reported here.
    End point type
    Secondary
    End point timeframe
    On Day 2
    End point values
    		 TIZASPRAY SIRDALUD ITT population Tizaspray ITT population Sirdalud PP population Tizaspray PP population Sirdalud
    Number of subjects analysed
    113
    112
    113
    112
    99
    105
    Units: mm
        arithmetic mean (standard deviation)
    -10.64 ( 12.53 )
    -7.07 ( 7.76 )
    -10.64 ( 12.53 )
    -7.07 ( 7.76 )
    -11.63 ( 12.65 )
    -7.32 ( 7.88 )
    Attachments
    		 Low back pain after 2nd dose (Day 2)
    Statistical analysis title
    		 T-test on Low back pain (ITT)
    Statistical analysis description
    T-test on low back pain after 2nd dose - Day 2 (ITT population)
    Comparison groups
    ITT population Tizaspray v ITT population Sirdalud
    Number of subjects included in analysis
    225
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.011 [29]
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.31
         upper limit
    		 -0.82
    Notes
    [29] - The difference between treatment groups was statistically significant at p<0.01667
    Statistical analysis title
    		 ANCOVA on Low back pain (ITT)
    Statistical analysis description
    ANCOVA on low back pain after 2nd dose - Day 2 (ITT population), with factors for treatment, site and baseline values
    Comparison groups
    ITT population Tizaspray v ITT population Sirdalud
    Number of subjects included in analysis
    225
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.011 [30]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.91
         upper limit
    		 -0.77
    Notes
    [30] - The difference between treatment groups was statistically significant at p<0.01667
    Statistical analysis title
    		 T-test on Low back pain (PP)
    Statistical analysis description
    T-test on low back pain after 2nd dose - Day 2 (PPpopulation)
    Comparison groups
    PP population Tizaspray v PP population Sirdalud
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0037 [31]
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -4.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.19
         upper limit
    		 -1.41
    Notes
    [31] - The difference between treatment groups was statistically significant at p<0.01
    Statistical analysis title
    		 ANCOVA on Low back pain (PP)
    Statistical analysis description
    ANCOVA on low back pain after 2nd dose - Day 2 (PP population), with factors for treatment, site and baseline values
    Comparison groups
    PP population Tizaspray v PP population Sirdalud
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0063 [32]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.44
         upper limit
    		 -1.07
    Notes
    [32] - The difference between treatment groups was statistically significant at p<0.01

    Secondary: Changes in Low Back Pain after 2nd dose (Day 3)

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    End point title
    		 Changes in Low Back Pain after 2nd dose (Day 3)
    End point description
    The differences between the moment of the second dose and after 30, 60, 90, 180 minutes have been estimated and analyzed. The difference between treatment groups was statistically significant after 30 and 60 minutes (p < 0.05), then the differences lowered. The analysis at 60 minutes is reported here.
    End point type
    Secondary
    End point timeframe
    On day 3
    End point values
    		 TIZASPRAY SIRDALUD ITT population Tizaspray ITT population Sirdalud PP population Tizaspray PP population Sirdalud
    Number of subjects analysed
    113
    111
    113
    111
    99
    105
    Units: mm
        arithmetic mean (standard deviation)
    -10.38 ( 10.04 )
    -7.51 ( 8.42 )
    -10.38 ( 10.04 )
    -7.51 ( 8.42 )
    -11.31 ( 9.70 )
    -7.45 ( 8.43 )
    Attachments
    		 Low back pain after 2nd dose (Day 3)
    Statistical analysis title
    		 T-test on Low back pain (ITT)
    Statistical analysis description
    T-test on low back pain after 2nd dose - Day 3 (ITT population)
    Comparison groups
    ITT population Tizaspray v ITT population Sirdalud
    Number of subjects included in analysis
    224
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0216 [33]
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.31
         upper limit
    		 -0.43
    Notes
    [33] - The difference between treatment groups was statistically significant at p<0.05
    Statistical analysis title
    		 ANCOVA on Low back pain (ITT)
    Statistical analysis description
    ANCOVA on low back pain after 2nd dose - Day 3 (ITT population), with factors for treatment, site and baseline values
    Comparison groups
    ITT population Tizaspray v ITT population Sirdalud
    Number of subjects included in analysis
    224
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0166 [34]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.3
         upper limit
    		 -0.54
    Notes
    [34] - The difference between treatment groups was statistically significant at p<0.01667
    Statistical analysis title
    		 T-test on Low back pain (PP)
    Statistical analysis description
    T-test on low back pain after 2nd dose - Day 3 (PP population)
    Comparison groups
    PP population Tizaspray v PP population Sirdalud
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0027 [35]
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.37
         upper limit
    		 -1.36
    Notes
    [35] - The difference between treatment groups was statistically significant at p<0.01
    Statistical analysis title
    		 ANCOVA on Low back pain (PP)
    Statistical analysis description
    ANCOVA on low back pain after 2nd dose - Day 3 (PP population), with factors for treatment, site and baseline values
    Comparison groups
    PP population Tizaspray v PP population Sirdalud
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0035 [36]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.09
         upper limit
    		 -1.21
    Notes
    [36] - The difference between treatment groups was statistically significant at p<0.01

    Secondary: Changes in Roland Disability Questionnaire

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    End point title
    		 Changes in Roland Disability Questionnaire
    End point description
    Changes in Roland Disability Questionnaire was administered between Day 1 and Day 8 have been estimated and compared between treatment groups.
    End point type
    Secondary
    End point timeframe
    Between Day 1 and Day 8
    End point values
    		 TIZASPRAY SIRDALUD ITT population Tizaspray ITT population Sirdalud PP population Tizaspray PP population Sirdalud
    Number of subjects analysed
    114
    114
    114
    114
    99
    106
    Units: points
        arithmetic mean (standard deviation)
    -8.95 ( 4.31 )
    -6.79 ( 3.86 )
    -8.95 ( 4.31 )
    -6.79 ( 3.86 )
    -8.95 ( 4.15 )
    -6.88 ( 3.83 )
    Attachments
    		 Changes in Rolad Disability Questionnaire (ITT)
    Statistical analysis title
    		 T-test on RDQ (ITT)
    Statistical analysis description
    T-test on Roland Disability Questionnaire (ITT population)
    Comparison groups
    ITT population Tizaspray v ITT population Sirdalud
    Number of subjects included in analysis
    228
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0001 [37]
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.23
         upper limit
    		 -1.09
    Notes
    [37] - The difference between treatment groups was statistically significant at p<0.001
    Statistical analysis title
    		 ANCOVA on RDQ (ITT)
    Statistical analysis description
    ANCOVA on Roland Disability Questionnaire (ITT population), with factors for treatment, site and baseline values
    Comparison groups
    ITT population Tizaspray v ITT population Sirdalud
    Number of subjects included in analysis
    228
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [38]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.75
         upper limit
    		 -1.09
    Notes
    [38] - The difference between treatment groups was statistically significant at p<0.001
    Statistical analysis title
    		 T-test on RDQ (PP)
    Statistical analysis description
    T-test on Roland Disability Questionnaire (PPpopulation)
    Comparison groups
    PP population Tizaspray v PP population Sirdalud
    Number of subjects included in analysis
    205
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0003 [39]
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.17
         upper limit
    		 -0.97
    Notes
    [39] - The difference between treatment groups was statistically significant at p<0.001
    Statistical analysis title
    		 ANCOVA on RDQ (PP)
    Statistical analysis description
    ANCOVA on Roland Disability Questionnaire (PP population), with factors for treatment, site and baseline values
    Comparison groups
    PP population Tizaspray v PP population Sirdalud
    Number of subjects included in analysis
    205
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [40]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.75
         upper limit
    		 -1.13
    Notes
    [40] - The difference between treatment groups was statistically significant at p<0.001

    Secondary: Changes in Schober's test

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    End point title
    		 Changes in Schober's test
    End point description
    Schober test difference in cm between day 1 and day 8
    End point type
    Secondary
    End point timeframe
    Between Day 1 and Day 8
    End point values
    		 TIZASPRAY SIRDALUD ITT population Tizaspray ITT population Sirdalud PP population Tizaspray PP population Sirdalud
    Number of subjects analysed
    114
    114
    114
    114
    99
    106
    Units: cm
        arithmetic mean (standard deviation)
    2.82 ( 1.55 )
    2.01 ( 2.00 )
    2.82 ( 1.55 )
    2.01 ( 2.00 )
    2.90 ( 1.56 )
    2.02 ( 1.34 )
    Attachments
    		 Changes in Schober test (ITT)
    Statistical analysis title
    		 T-test on Schober's test (ITT)
    Statistical analysis description
    T-test on Schober's test (ITT population)
    Comparison groups
    ITT population Tizaspray v ITT population Sirdalud
    Number of subjects included in analysis
    228
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [41]
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.43
         upper limit
    		 1.19
    Notes
    [41] - The difference between treatment groups was statistically significant at p<0.001
    Statistical analysis title
    		 ANCOVA on Schober's test (ITT)
    Statistical analysis description
    ANCOVA on Schober's test (ITT population), with factors for treatment, site and baseline values
    Comparison groups
    ITT population Tizaspray v ITT population Sirdalud
    Number of subjects included in analysis
    228
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [42]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.44
         upper limit
    		 1.08
    Notes
    [42] - The difference between treatment groups was statistically significant at p<0.001
    Statistical analysis title
    		 T-test on Schober's test (PP)
    Statistical analysis description
    T-test on Schober's test (PP population)
    Comparison groups
    PP population Tizaspray v PP population Sirdalud
    Number of subjects included in analysis
    205
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [43]
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.48
         upper limit
    		 1.28
    Notes
    [43] - The difference between treatment groups was statistically significant at p<0.001
    Statistical analysis title
    		 ANCOVA on Schober's test (PP)
    Statistical analysis description
    ANCOVA on Schober's test (PP population), with factors for treatment, site and baseline values
    Comparison groups
    PP population Tizaspray v PP population Sirdalud
    Number of subjects included in analysis
    205
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [44]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.42
         upper limit
    		 1.1
    Notes
    [44] - The difference between treatment groups was statistically significant at p<0.001

    Secondary: Number of patients taking paracetamol tablets

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    End point title
    		 Number of patients taking paracetamol tablets
    End point description
    The number of patients that have taken paracetamol tablets during the study was compared between treatment groups
    End point type
    Secondary
    End point timeframe
    Between Day 1 and Day 8
    End point values
    		 TIZASPRAY SIRDALUD ITT population Tizaspray ITT population Sirdalud PP population Tizaspray PP population Sirdalud
    Number of subjects analysed
    112
    113
    112
    113
    98
    104
    Units: tablets
    67
    79
    67
    79
    59
    72
    Statistical analysis title
    		 Chi-square test on patients took paracetamol (ITT)
    Statistical analysis description
    Chi-square test on the number of patients that have taken any paracetamol tablets during the study (ITT)
    Comparison groups
    ITT population Tizaspray v ITT population Sirdalud
    Number of subjects included in analysis
    225
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1129 [45]
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [45] - The difference between treatment groups was not statistically significant
    Statistical analysis title
    		 Logistic reg. on patients took paracetamol (ITT)
    Statistical analysis description
    Logistic regression on the number of patients that have taken any paracetamol tablets during the study (ITT), with factors for treatment and site
    Comparison groups
    ITT population Tizaspray v ITT population Sirdalud
    Number of subjects included in analysis
    225
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0678 [46]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.32
         upper limit
    		 1.04
    Notes
    [46] - The difference between treatment groups was not statistically significant
    Statistical analysis title
    		 Chi-square test on patients took paracetamol (PP)
    Statistical analysis description
    Chi-square test on the number of patients that have taken any paracetamol tablets during the study (PP)
    Comparison groups
    PP population Tizaspray v PP population Sirdalud
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1793 [47]
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [47] - The difference between treatment groups was not statistically significant
    Statistical analysis title
    		 Logistic reg. on patients took paracetamol (PP)
    Statistical analysis description
    Logistic regression on the number of patients that have taken any paracetamol tablets during the study (PP), with factors for treatment and site
    Comparison groups
    PP population Tizaspray v PP population Sirdalud
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1083 [48]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.31
         upper limit
    		 1.12
    Notes
    [48] - The difference between treatment groups was not statistically significant

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Between Day 1 (Baseline) and Day 8 (end of treatment/end of study)
    Adverse event reporting additional description
    The reporting period for AEs was the period between the time of Informed Consent signature and day 8 (+2). At the end of this follow-up period, all unresolved AEs were documented on the CRF as “ongoing”.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    TIZASPRAY
    Reporting group description
    		 Patients treated with Tizaspray® nasal solution

    Reporting group title
    SIRDALUD
    Reporting group description
    		 Patients treated with Sirdalud® 2mg oral tablets

    Serious adverse events
    		 TIZASPRAY SIRDALUD
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 118 (0.00%)
    0 / 116 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 TIZASPRAY SIRDALUD
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 118 (10.17%)
    6 / 116 (5.17%)
    Vascular disorders
    Dizziness
         subjects affected / exposed
    2 / 118 (1.69%)
    1 / 116 (0.86%)
         occurrences all number
    2
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 116 (0.00%)
         occurrences all number
    1
    0
    Headache
         subjects affected / exposed
    1 / 118 (0.85%)
    1 / 116 (0.86%)
         occurrences all number
    1
    1
    Somnolence
         subjects affected / exposed
    3 / 118 (2.54%)
    3 / 116 (2.59%)
         occurrences all number
    3
    3
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 116 (0.86%)
         occurrences all number
    0
    1
    Burning sensation
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 116 (0.00%)
         occurrences all number
    1
    0
    Fatigue
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 116 (0.86%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Aphthous ulcer
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 116 (0.00%)
         occurrences all number
    1
    0
    Dry mouth
         subjects affected / exposed
    1 / 118 (0.85%)
    2 / 116 (1.72%)
         occurrences all number
    1
    2
    Nausea
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 116 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Nasal discomfort
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 116 (0.00%)
         occurrences all number
    3
    0
    Nasal pruritus
         subjects affected / exposed
    2 / 118 (1.69%)
    0 / 116 (0.00%)
         occurrences all number
    6
    0
    Psychiatric disorders
    Disturbance in attention
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 116 (0.86%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 116 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 May 2015
    The amendment no. 2 to the Protocol concerned the changes of some eligibility criteria, in particular Exclusion Criterion No.13 and Inclusion Criterion No. 4, modified also taking into account the opinion of the Italian Investigators.
    09 Dec 2015
    The Amendment no. 3 was aimed at reducing the blood tests from 2 to just 1, maintaining only the baseline blood draw.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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