Chronic Troublesome Sialorrhea, Parkinson's Disease, Post-stroke, Traumatic Brain Injury
Conditions
Brief summary
The objective of this study is to investigate the efficacy and safety of two different dose levels of NT 201 (75 U or 100 U per cycle), compared with placebo, in reducing the salivary flow rate, and the severity and frequency of chronic troublesome sialorrhea that occurs as a result of various neurological conditions in adult subjects.
Interventions
Active ingredient: Clostridium Botulinum neurotoxin Type A free from complexing proteins. Solution for injection prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl).
DRUGIncobotulinumtoxinA (75 Units)
Active ingredient: Clostridium Botulinum neurotoxin Type A free from complexing proteins. Solution for injection prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl).
DRUGPlacebo
Solution for injection prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl).
Sponsors
Merz Pharmaceuticals GmbH
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Documented diagnosis of the basic neurological condition associated with sialorrhea (as above, (i), (ii) or (iii); with onset at least 6 months before screening). * Chronic troublesome sialorrhea related to parkinsonism or stroke or traumatic brain injury (for at least 3 months) at screening, defined as the presence of all of the following, at screening and at baseline and for at least the 3 months before screening (where retrospective response to questionnaires is impossible, a statement of equivalent severity will suffice): 1. A Drooling Severity and Frequency Scale \[DSFS\] sum score of at least 6 points and 2. A score of at least 2 points for each item of the DSFS and 3. A score of at least 3 points on the modified Radboud Oral Motor Inventory for Parkinson's Disease \[mROMP\], Section 'III Drooling', Item A). * A score of at most 2 points on the mROMP Section 'II Swallowing Symptoms' Item A) and a score of at most 3 points on Item C), at screening and at baseline.
Exclusion criteria
* Non-neurological secondary causes of sialorrhea. * Unstable concomitant medication influencing sialorrhea (such as anticholinergics for the treatment of parkinsonism; dosages of these medications must have been stable for at least 4 weeks before study entry, i.e. screening, and must be planned to remain stable during the course of the study. * Recent (i.e., four weeks) drug treatment for sialorrhea. * History of recurrent aspiration pneumonia. * Extremely poor dental/oral condition as assessed by a qualified dentist. * Recent (i.e., one year for sialorrhea, 14 weeks for other indications) treatment with - or known hypersensitivity to - Botulinum toxin, or known hypersensitivity to any ingredient of the study preparation. * Recent (i.e., four weeks) changes in anti-parkinsonian medication. * Previous or planned surgery or irradiation to control sialorrhea.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| MP: Change From Baseline in Unstimulated Salivary Flow (uSFR) Rate at Week 4 | Baseline and Week 4 | uSFR was assessed by weighing of dental rolls soaked with saliva over 5 minutes and then procedure was repeated after 30 minutes and the average of the 2 results for flow rate was calculated. |
| MP: Participant's Global Impression of Change Scale (GICS) at Week 4 | Week 4 | The GICS was used to measure the impression of change due to treatment. The response option was a common 7-point Likert scale that ranged from -3 = very much worse to +3 = very much improved and was applicable for participant and caregiver. If the participant was not able to answer then carer's rating was to be recorded instead of participant's rating and the participant's rating was left blank. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| MP: Change From Baseline in Unstimulated Salivary Flow (uSFR) Rate at Week 8 and 12 | Baseline, Week 8 and 12 | uSFR was assessed by weighing of dental rolls soaked with saliva over 5 minutes and then procedure was repeated after 30 minutes and the average of the 2 results for flow rate was calculated. |
| MP: Global Impression of Change Scale (GICS) at Week 1, 2, 8 and 12 | Week 1, 2, 8, and 12 | The GICS was used to measure the investigator's impression of change due to treatment. The response option was a common 7-point Likert scale that ranged from -3 = very much worse to +3 = very much improved and was applicable for participant and caregiver. If the participant was not able to answer then carer's rating was to be recorded instead of participant's rating and the participant's rating was left blank. |
Countries
Germany, Poland
Participant flow
Recruitment details
The study was conducted at 12 sites in Poland and Germany.
Pre-assignment details
A total of 216 participants were screened for the study, of which 184 participants were randomized and treated in the Main Period (MP) of the study. A total of 173 participants who completed the MP, entered the 2 treatment arms of the Extension Period (EP) of the study.
Participants by arm
| Arm | Count |
|---|---|
| MP: Placebo Participants received one injection session of overall 2.0 mL placebo matched to the volume of incobotulinumtoxinA via bilateral intraglandular injection into the parotid and submandibular glands on Day 1 in the MP. | 36 |
| MP: IncobotulinumtoxinA (Xeomin) (75 Units) Participants received one injection session of overall 2.0 mL incobotulinumtoxinA containing 75 units via bilateral intraglandular injection into the parotid and submandibular glands on Day 1 in the MP. | 74 |
| MP: IncobotulinumtoxinA (Xeomin) (100 Units) Participants received one injection session of overall 2.0 mL incobotulinumtoxinA containing 100 units via bilateral intraglandular injection into the parotid and submandibular glands on Day 1 in the MP. | 74 |
| Total | 184 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| EP: 48 Weeks | Adverse Event | 0 | 0 | 0 | 2 | 6 |
| EP: 48 Weeks | Death | 0 | 0 | 0 | 3 | 2 |
| EP: 48 Weeks | Other | 0 | 0 | 0 | 1 | 0 |
| EP: 48 Weeks | Withdrawal by Subject | 0 | 0 | 0 | 2 | 6 |
| MP: 16 Weeks | Adverse Event | 1 | 1 | 1 | 0 | 0 |
| MP: 16 Weeks | Lost to Follow-up | 0 | 0 | 1 | 0 | 0 |
| MP: 16 Weeks | Withdrawal by Subject | 3 | 4 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | MP: Placebo | MP: IncobotulinumtoxinA (Xeomin) (75 Units) | MP: IncobotulinumtoxinA (Xeomin) (100 Units) | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 17 Participants | 44 Participants | 46 Participants | 107 Participants |
| Age, Categorical Between 18 and 65 years | 19 Participants | 30 Participants | 28 Participants | 77 Participants |
| Body Mass Index (BMI) | 28.5 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 6 | 26.7 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 5.2 | 27.7 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 3.8 | 27.5 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 4.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 36 Participants | 74 Participants | 73 Participants | 183 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 36 Participants | 74 Participants | 73 Participants | 183 Participants |
| Sex: Female, Male Female | 8 Participants | 24 Participants | 22 Participants | 54 Participants |
| Sex: Female, Male Male | 28 Participants | 50 Participants | 52 Participants | 130 Participants |
| Weight | 80.6 kilogram (kg) STANDARD_DEVIATION 16.4 | 78.4 kilogram (kg) STANDARD_DEVIATION 17.1 | 79.8 kilogram (kg) STANDARD_DEVIATION 14 | 79.4 kilogram (kg) STANDARD_DEVIATION 15.7 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 36 | 0 / 74 | 0 / 74 | 3 / 82 | 2 / 89 |
| other Total, other adverse events | 2 / 36 | 14 / 74 | 10 / 74 | 22 / 82 | 22 / 89 |
| serious Total, serious adverse events | 3 / 36 | 6 / 74 | 9 / 74 | 15 / 82 | 14 / 89 |
Outcome results
Primary
MP: Change From Baseline in Unstimulated Salivary Flow (uSFR) Rate at Week 4
uSFR was assessed by weighing of dental rolls soaked with saliva over 5 minutes and then procedure was repeated after 30 minutes and the average of the 2 results for flow rate was calculated.
Time frame: Baseline and Week 4
Population: Analysis covers all participants from FAS who have at least one post-baseline uSFR assessment. The FAS is the subset of participants who were treated and had at least the baseline value of uSFR.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MP: Placebo | MP: Change From Baseline in Unstimulated Salivary Flow (uSFR) Rate at Week 4 | -0.04 gram per minute (g/min) | Standard Error 0.033 |
| MP: IncobotulinumtoxinA (Xeomin) (75 Units) | MP: Change From Baseline in Unstimulated Salivary Flow (uSFR) Rate at Week 4 | -0.06 gram per minute (g/min) | Standard Error 0.027 |
| MP: IncobotulinumtoxinA (Xeomin) (100 Units) | MP: Change From Baseline in Unstimulated Salivary Flow (uSFR) Rate at Week 4 | -0.13 gram per minute (g/min) | Standard Error 0.026 |
Comparison: A fixed sequence test procedure was used for the confirmatory analysis of the co-primary endpoints by comparing the least square (LS) means estimates of an mixed model repeated measurement (MMRM) model (2-sided, significance level alpha=0.05) between treatment groups in the following order:~1. IncobotulinumtoxinA 100 units versus (v) Placebo~2. IncobotulinumtoxinA 75 units v Placebop-value: =0.00495% CI: [-0.15, 0.03]MMRM
Comparison: A fixed sequence test procedure was used for the confirmatory analysis of the co-primary endpoints by comparing the least square means estimates of an MMRM model (2-sided, significance level alpha=0.05) between treatment groups in the following order:~1. IncobotulinumtoxinA 100 units v Placebo~2. IncobotulinumtoxinA 75 units v Placebop-value: =0.54295% CI: [-0.08, 0.04]MMRM
Primary
MP: Participant's Global Impression of Change Scale (GICS) at Week 4
The GICS was used to measure the impression of change due to treatment. The response option was a common 7-point Likert scale that ranged from -3 = very much worse to +3 = very much improved and was applicable for participant and caregiver. If the participant was not able to answer then carer's rating was to be recorded instead of participant's rating and the participant's rating was left blank.
Time frame: Week 4
Population: The FAS is the subset of participants who were treated and had at least the baseline value of uSFR.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MP: Placebo | MP: Participant's Global Impression of Change Scale (GICS) at Week 4 | 0.67 units on a scale | Standard Error 0.186 |
| MP: IncobotulinumtoxinA (Xeomin) (75 Units) | MP: Participant's Global Impression of Change Scale (GICS) at Week 4 | 1.02 units on a scale | Standard Error 0.148 |
| MP: IncobotulinumtoxinA (Xeomin) (100 Units) | MP: Participant's Global Impression of Change Scale (GICS) at Week 4 | 1.25 units on a scale | Standard Error 0.144 |
Comparison: A fixed sequence test procedure was used for the confirmatory analysis of the co-primary endpoints by comparing the least square means estimates of an MMRM model (2-sided, significance level alpha=0.05) between treatment groups in the following order:~1. IncobotulinumtoxinA 100 units v Placebo~2. IncobotulinumtoxinA 75 units v Placebop-value: =0.00295% CI: [0.22, 0.94]MMRM
Comparison: A fixed sequence test procedure was used for the confirmatory analysis of the co-primary endpoints by comparing the least square means estimates of an MMRM model (2-sided, significance level alpha=0.05) between treatment groups in the following order:~1. IncobotulinumtoxinA 100 units v Placebo~2. IncobotulinumtoxinA 75 units v Placebop-value: =0.05595% CI: [-0.01, 0.71]MMRM
Secondary
MP: Change From Baseline in Unstimulated Salivary Flow (uSFR) Rate at Week 8 and 12
uSFR was assessed by weighing of dental rolls soaked with saliva over 5 minutes and then procedure was repeated after 30 minutes and the average of the 2 results for flow rate was calculated.
Time frame: Baseline, Week 8 and 12
Population: Analysis covers all participants from FAS who have at least one post-baseline uSFR assessment. The FAS is the subset of participants who were treated and had at least the baseline value of uSFR.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| MP: Placebo | MP: Change From Baseline in Unstimulated Salivary Flow (uSFR) Rate at Week 8 and 12 | Week 8 | -0.02 g/min | Standard Error 0.033 |
| MP: Placebo | MP: Change From Baseline in Unstimulated Salivary Flow (uSFR) Rate at Week 8 and 12 | Week 12 | -0.03 g/min | Standard Error 0.033 |
| MP: IncobotulinumtoxinA (Xeomin) (75 Units) | MP: Change From Baseline in Unstimulated Salivary Flow (uSFR) Rate at Week 8 and 12 | Week 8 | -0.08 g/min | Standard Error 0.027 |
| MP: IncobotulinumtoxinA (Xeomin) (75 Units) | MP: Change From Baseline in Unstimulated Salivary Flow (uSFR) Rate at Week 8 and 12 | Week 12 | -0.1 g/min | Standard Error 0.027 |
| MP: IncobotulinumtoxinA (Xeomin) (100 Units) | MP: Change From Baseline in Unstimulated Salivary Flow (uSFR) Rate at Week 8 and 12 | Week 8 | -0.13 g/min | Standard Error 0.026 |
| MP: IncobotulinumtoxinA (Xeomin) (100 Units) | MP: Change From Baseline in Unstimulated Salivary Flow (uSFR) Rate at Week 8 and 12 | Week 12 | -0.12 g/min | Standard Error 0.026 |
Secondary
MP: Global Impression of Change Scale (GICS) at Week 1, 2, 8 and 12
The GICS was used to measure the investigator's impression of change due to treatment. The response option was a common 7-point Likert scale that ranged from -3 = very much worse to +3 = very much improved and was applicable for participant and caregiver. If the participant was not able to answer then carer's rating was to be recorded instead of participant's rating and the participant's rating was left blank.
Time frame: Week 1, 2, 8, and 12
Population: The FAS is the subset of participants who were treated and had at least the baseline value of uSFR.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| MP: Placebo | MP: Global Impression of Change Scale (GICS) at Week 1, 2, 8 and 12 | Week 8 | 0.47 units on a scale | Standard Error 0.192 |
| MP: Placebo | MP: Global Impression of Change Scale (GICS) at Week 1, 2, 8 and 12 | Week 2 | 0.83 units on a scale | Standard Error 0.178 |
| MP: Placebo | MP: Global Impression of Change Scale (GICS) at Week 1, 2, 8 and 12 | Week 12 | 0.56 units on a scale | Standard Error 0.197 |
| MP: Placebo | MP: Global Impression of Change Scale (GICS) at Week 1, 2, 8 and 12 | Week 1 | 0.67 units on a scale | Standard Error 0.17 |
| MP: IncobotulinumtoxinA (Xeomin) (75 Units) | MP: Global Impression of Change Scale (GICS) at Week 1, 2, 8 and 12 | Week 12 | 0.98 units on a scale | Standard Error 0.156 |
| MP: IncobotulinumtoxinA (Xeomin) (75 Units) | MP: Global Impression of Change Scale (GICS) at Week 1, 2, 8 and 12 | Week 2 | 0.91 units on a scale | Standard Error 0.143 |
| MP: IncobotulinumtoxinA (Xeomin) (75 Units) | MP: Global Impression of Change Scale (GICS) at Week 1, 2, 8 and 12 | Week 8 | 1.07 units on a scale | Standard Error 0.151 |
| MP: IncobotulinumtoxinA (Xeomin) (75 Units) | MP: Global Impression of Change Scale (GICS) at Week 1, 2, 8 and 12 | Week 1 | 0.73 units on a scale | Standard Error 0.138 |
| MP: IncobotulinumtoxinA (Xeomin) (100 Units) | MP: Global Impression of Change Scale (GICS) at Week 1, 2, 8 and 12 | Week 2 | 1.11 units on a scale | Standard Error 0.139 |
| MP: IncobotulinumtoxinA (Xeomin) (100 Units) | MP: Global Impression of Change Scale (GICS) at Week 1, 2, 8 and 12 | Week 1 | 0.96 units on a scale | Standard Error 0.133 |
| MP: IncobotulinumtoxinA (Xeomin) (100 Units) | MP: Global Impression of Change Scale (GICS) at Week 1, 2, 8 and 12 | Week 8 | 1.3 units on a scale | Standard Error 0.148 |
| MP: IncobotulinumtoxinA (Xeomin) (100 Units) | MP: Global Impression of Change Scale (GICS) at Week 1, 2, 8 and 12 | Week 12 | 1.21 units on a scale | Standard Error 0.152 |