Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability

Study Overview
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Brief Summary
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The objective of this study is to investigate the efficacy and safety of NT 201 compared with placebo for the treatment of chronic troublesome sialorrhea associated with neurological disorders (e.g. cerebral palsy, traumatic brain injury) and/or intellectual disability in children and adolescents naïve to Botulinum neurotoxin treatment and aged 2-17 years.

Official Title
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Prospective, Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter Study With an Open-label Extension Period to Investigate the Efficacy and Safety of NT 201 in the Treatment of Children and Adolescents (2-17 Years) With Chronic Troublesome Sialorrhea Associated With Neurological Disorders, and/or Intellectual Disability

Conditions
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Stroke, Chronic Troublesome Sialorrhea, Cerebral Palsy, Traumatic Brain Injury, Intellectual Disability

Intervention / Treatment
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* Drug: NT 201 Placebo
* Drug: NT 201


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female child/adolescent age 2-17 years. Any neurological disorder (e.g. cerebral palsy or traumatic brain injury) and/or intellectual disability associated with chronic troublesome sialorrhea for at least 3 months up to the screening. In subjects with intellectual disability (ID) without neurological disorders, a diagnosis of ID by a specialist, e.g. pediatrician or by a center for developmental medicine is required for inclusion. Severe drooling (modified Teacher´s Drooling Scale [mTDS] ≥ 6; clothing occasionally becomes damp) as rated by the investigator. Parental consent and the subject's oral or written assent as the subject is able to provide. Exclusion Criteria: Chronic troublesome sialorrhea not related to neurological disorders and/or intellectual disability. Body weight < 12 kg. Pharmacological treatment for sialorrhea or concomitant medication known to influence sialorrhea strongly (e.g. anticholinergics with exception of locally applied or short acting drugs used under general anesthesia) within 45 days before baseline and during the entire study period. Any previous known or suspected hypersensitivity to Botulinum toxin. Aspiration pneumonia within 6 month before screening. Any previous treatment with Botulinum toxin for any body region during the year before screening or within the screening period Prior, concomitant or planned surgery or irradiation to head and neck to control sialorrhea (including salivary gland surgery or salivary gland irradiation) within one year before screening or planned for any part of the entire study period. Concurrent diseases, including hematological, hepatic, renal, gastrointestinal, endocrine, pulmonary, musculoskeletal, or psychiatric diseases or conditions, which in the judgment of the investigator would put the subject at risk while in the study, could influence the results of the study, or negatively impact the subject's ability to participate in the study. Extremely poor dental and/or oral condition that might preclude safe study participation by the judgment of the investigator. Nursing mother or pregnant female subject.

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Double-blind MP: Placebo (Age 6 to 17 Years)<br>Participants will receive placebo via bilateral intraglandular injection into the parotid and submandibular glands in one injection session on Day 1 (Visit 2) of the MP, followed by an observation period of 16 weeks. Volumes will be matched to the volumes of NT 201 (incobotulinumtoxinA; Xeomin) injected in the experimental arm. | Drug: NT 201 Placebo<br>* NT 201 placebo matching injection.<br>|
| Experimental: Double-blind, MP: NT 201 (Age 6 to 17 Years)<br>Participants will receive NT 201 (up to 2.5 Units per kilogram [U/kg] body weight) via bilateral intraglandular injection into the parotid and submandibular glands in one injection session on Day 1 (Visit 2) of the MP, followed by an observation period of 16 weeks. | Drug: NT 201<br>* NT 201 injection.<br>* Other names: Botulinum toxin type A (150 kiloDalton), free from complexing proteins;|
| Experimental: Open-label, MP: NT 201 (Age 2 to 5 Years)<br>Participants will receive NT 201 (about 1.5-2 U/kg body weight) via bilateral intraglandular injection into the parotid and submandibular glands in one injection session on Day 1 (Visit 2) of the MP, followed by an observation period of 16 weeks. | Drug: NT 201<br>* NT 201 injection.<br>* Other names: Botulinum toxin type A (150 kiloDalton), free from complexing proteins;|
| Experimental: OLEX: NT 201 (Age 6 to 17 Years)<br>Participants will receive NT 201 (up to 2.5 U/kg body weight) via bilateral intraglandular injection into the parotid and submandibular glands on Day 1 of second (Visit 6), third (Visit 10), and fourth (Visit 14) injection cycle of the OLEX, followed by an observation period of 16 weeks each (48 weeks in total). This arm will consist of participants who will participate in MP arms Double-blind, MP: placebo (age 6 to 17 years) and Double-blind, MP: NT 201 (age 6 to 17 years). | Drug: NT 201<br>* NT 201 injection.<br>* Other names: Botulinum toxin type A (150 kiloDalton), free from complexing proteins;|
| Experimental: OLEX: NT 201 (Age 2 to 5 Years)<br>Participants will receive NT 201 (about 1.5-2 U/kg body weight) via bilateral intraglandular injection into the parotid and submandibular glands on Day 1 of second (Visit 6), third (Visit 10), and fourth (Visit 14) injection cycle of the OLEX, followed by an observation period of 16 weeks each (48 weeks in total). | Drug: NT 201<br>* NT 201 injection.<br>* Other names: Botulinum toxin type A (150 kiloDalton), free from complexing proteins;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Unstimulated Salivary Flow Rate (uSFR) at Week 4 | This endpoint was planned to be analyzed in double-blind, MP, 6 to 17 years participants only. uSFR was assessed by weighing of absorbent swabs with safety threads soaked with saliva over 5 minutes and the procedure was repeated after 30 minutes. Salivary flow rate was equal to weight increase of swabs/time of collection. The average of the 2 results for flow rate was calculated. The reduction of measured weight over the study relates to improvement of sialorrhea. | Baseline and Week 4 | 
| Global Impression of Change Scale (GICS) at Week 4 Assessed by the Carer/Parent(s) | This endpoint was analyzed in double-blind, MP, 6 to 17 years participants. The GICS was used to measure the carer's/parent's impression of change due to treatment. The response option was a common 7-point Likert scale, with the following values: +3 (very much improved); +2 (much improved); +1 (minimally improved); 0 (no change); -1 (minimally worse); -2 (much worse); -3 (very much worse). | Week 4 | 
| Occurrence of Treatment Emergent Adverse Events (TEAEs) Overall and Per Injection Cycle |  | Baseline up to Week 64 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in uSFR at Weeks 8 and 12 | This endpoint was analyzed in double-blind, MP, 6 to 17 years participants. uSFR was assessed by weighing of absorbent swabs with safety threads soaked with saliva over 5 minutes and then procedure was repeated after 30 minutes. Salivary flow rate was equal to weight increase of swabs/time of collection. The average of the 2 results for flow rate was calculated. The reduction of measured weight over the study relates to improvement of sialorrhea. | Baseline and Weeks 8 and 12 | 
| GICS at Weeks 8 and 12 | This endpoint was analyzed in double-blind, MP, 6 to 17 years participants. The GICS was used to measure the carer's/parent's impression of change due to treatment. The response option was a common 7-point Likert scale with the following values: +3 (very much improved); +2 (much improved); +1 (minimally improved); 0 (no change); -1 (minimally worse); -2 (much worse); -3 (very much worse). | Weeks 8 and 12 | 
| Occurrence of Treatment Emergent Adverse Events of Special Interest (AESI) Overall and by Injection Cycle |  | Baseline up to Week 64 | 
| Occurrence of Treatment Emergent Serious Adverse Events (TESAEs) Overall and by Injection Cycle |  | Baseline up to Week 64 | 
| Occurrence of TEAEs Related to Treatment as Assessed by the Investigator Overall and by Injection Cycle |  | Baseline up to Week 64 | 
| Occurrence of TEAEs Leading to Discontinuation Overall and by Injection Cycle |  | Baseline up to Week 64 |