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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 (SIPEXI)

Primary Purpose

Chronic Troublesome Sialorrhea, Cerebral Palsy, Stroke

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
NT 201 Placebo
NT 201
Sponsored by
Merz Pharmaceuticals GmbH
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Chronic Troublesome Sialorrhea

Eligibility Criteria

2 Years - 17 Years (Child)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Merz Investigational Site #9950003
  • Merz Investigational Site #9950001
  • Merz Investigational Site #9950002
  • Merz Investigational Site #0360017
  • Merz Investigational Site #0360013
  • Merz Investigational Site # 0360014
  • Merz Investigational Site # 0360015
  • Merz Investigational Site #0360018
  • Merz Investigational Site #0360016
  • Merz Investigational Site #0480092
  • Merz Investigational Site #0480090
  • Merz Investigational Site #0480076
  • Merz Investigational Site #0480059
  • Merz Investigational Site #0480060
  • Merz Investigational Site #0070016
  • Merz Investigational Site # 0070288
  • Merz Investigational Site #0070290
  • Merz Investigational # 0070017
  • Merz Investigational Site #0070013
  • Merz Investigational Site # 070019
  • Merz Investigational Site #0070300
  • Merz Investigational Site #0070301
  • Merz Investigational Site #3810001
  • Merz Investigational Site #3800001
  • Merz Investigational Site #3800012
  • Merz Investigational Site #3800005
  • Merz Investigational Site #3800007
  • Merz Investigational Site #3800013
  • Merz Investigational site #3800003
  • Merz Investigational Site #3800009
  • Merz Investigational Site #3800011

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

Double-blind MP: Placebo (Age 6 to 17 Years)

Double-blind, MP: NT 201 (Age 6 to 17 Years)

Open-label, MP: NT 201 (Age 2 to 5 Years)

OLEX: NT 201 (Age 6 to 17 Years)

OLEX: NT 201 (Age 2 to 5 Years)

Arm Description

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.

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.

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.

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)".

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).

Outcomes

Primary Outcome Measures

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.
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).
Occurrence of Treatment Emergent Adverse Events (TEAEs) Overall and Per Injection Cycle

Secondary Outcome Measures

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.
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).
Occurrence of Treatment Emergent Adverse Events of Special Interest (AESI) Overall and by Injection Cycle
Occurrence of Treatment Emergent Serious Adverse Events (TESAEs) Overall and by Injection Cycle
Occurrence of TEAEs Related to Treatment as Assessed by the Investigator Overall and by Injection Cycle
Occurrence of TEAEs Leading to Discontinuation Overall and by Injection Cycle

Full Information

First Posted
October 17, 2014
Last Updated
August 6, 2021
Sponsor
Merz Pharmaceuticals GmbH
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1. Study Identification

Unique Protocol Identification Number
NCT02270736
Brief Title
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
Acronym
SIPEXI
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
July 2019
Overall Recruitment Status
Completed
Study Start Date
February 9, 2015 (Actual)
Primary Completion Date
February 23, 2018 (Actual)
Study Completion Date
May 7, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Merz Pharmaceuticals GmbH

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Troublesome Sialorrhea, Cerebral Palsy, Stroke, Traumatic Brain Injury, Intellectual Disability

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
256 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Double-blind MP: Placebo (Age 6 to 17 Years)
Arm Type
Experimental
Arm Description
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.
Arm Title
Double-blind, MP: NT 201 (Age 6 to 17 Years)
Arm Type
Experimental
Arm Description
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.
Arm Title
Open-label, MP: NT 201 (Age 2 to 5 Years)
Arm Type
Experimental
Arm Description
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.
Arm Title
OLEX: NT 201 (Age 6 to 17 Years)
Arm Type
Experimental
Arm Description
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)".
Arm Title
OLEX: NT 201 (Age 2 to 5 Years)
Arm Type
Experimental
Arm Description
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).
Intervention Type
Drug
Intervention Name(s)
NT 201 Placebo
Intervention Description
NT 201 placebo matching injection.
Intervention Type
Drug
Intervention Name(s)
NT 201
Other Intervention Name(s)
IncobotulinumtoxinA, Xeomin, Botulinum toxin type A (150 kiloDalton), free from complexing proteins
Intervention Description
NT 201 injection.
Primary Outcome Measure Information:
Title
Change From Baseline in Unstimulated Salivary Flow Rate (uSFR) at Week 4
Description
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.
Time Frame
Baseline and Week 4
Title
Global Impression of Change Scale (GICS) at Week 4 Assessed by the Carer/Parent(s)
Description
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).
Time Frame
Week 4
Title
Occurrence of Treatment Emergent Adverse Events (TEAEs) Overall and Per Injection Cycle
Time Frame
Baseline up to Week 64
Secondary Outcome Measure Information:
Title
Change From Baseline in uSFR at Weeks 8 and 12
Description
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.
Time Frame
Baseline and Weeks 8 and 12
Title
GICS at Weeks 8 and 12
Description
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).
Time Frame
Weeks 8 and 12
Title
Occurrence of Treatment Emergent Adverse Events of Special Interest (AESI) Overall and by Injection Cycle
Time Frame
Baseline up to Week 64
Title
Occurrence of Treatment Emergent Serious Adverse Events (TESAEs) Overall and by Injection Cycle
Time Frame
Baseline up to Week 64
Title
Occurrence of TEAEs Related to Treatment as Assessed by the Investigator Overall and by Injection Cycle
Time Frame
Baseline up to Week 64
Title
Occurrence of TEAEs Leading to Discontinuation Overall and by Injection Cycle
Time Frame
Baseline up to Week 64

10. Eligibility

Sex
All
Minimum Age & Unit of Time
2 Years
Maximum Age & Unit of Time
17 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Merz Medical Expert
Organizational Affiliation
Merz Pharmaceuticals GmbH
Official's Role
Study Director
Facility Information:
Facility Name
Merz Investigational Site #9950003
City
Kobuleti
ZIP/Postal Code
6200
Country
Georgia
Facility Name
Merz Investigational Site #9950001
City
Tbilisi
ZIP/Postal Code
0159
Country
Georgia
Facility Name
Merz Investigational Site #9950002
City
Tbilisi
ZIP/Postal Code
0159
Country
Georgia
Facility Name
Merz Investigational Site #0360017
City
Balassagyarmat
ZIP/Postal Code
2660
Country
Hungary
Facility Name
Merz Investigational Site #0360013
City
Budapest
ZIP/Postal Code
1083
Country
Hungary
Facility Name
Merz Investigational Site # 0360014
City
Budapest
ZIP/Postal Code
1125
Country
Hungary
Facility Name
Merz Investigational Site # 0360015
City
Budapest
ZIP/Postal Code
1125
Country
Hungary
Facility Name
Merz Investigational Site #0360018
City
Budapest
ZIP/Postal Code
1146
Country
Hungary
Facility Name
Merz Investigational Site #0360016
City
Szombathely
ZIP/Postal Code
9700
Country
Hungary
Facility Name
Merz Investigational Site #0480092
City
Bialystok
ZIP/Postal Code
15-274
Country
Poland
Facility Name
Merz Investigational Site #0480090
City
Gdansk
ZIP/Postal Code
80-952
Country
Poland
Facility Name
Merz Investigational Site #0480076
City
Katowice
ZIP/Postal Code
40-954
Country
Poland
Facility Name
Merz Investigational Site #0480059
City
Krakow
ZIP/Postal Code
30-359
Country
Poland
Facility Name
Merz Investigational Site #0480060
City
Wiazowna
ZIP/Postal Code
05-462
Country
Poland
Facility Name
Merz Investigational Site #0070016
City
Kazan
ZIP/Postal Code
420012
Country
Russian Federation
Facility Name
Merz Investigational Site # 0070288
City
Kemerovo
ZIP/Postal Code
650066
Country
Russian Federation
Facility Name
Merz Investigational Site #0070290
City
Khabarovsk
ZIP/Postal Code
680038
Country
Russian Federation
Facility Name
Merz Investigational # 0070017
City
Saint Petersburg
ZIP/Postal Code
194100
Country
Russian Federation
Facility Name
Merz Investigational Site #0070013
City
Smolensk
ZIP/Postal Code
214018
Country
Russian Federation
Facility Name
Merz Investigational Site # 070019
City
Stavropol
ZIP/Postal Code
355029
Country
Russian Federation
Facility Name
Merz Investigational Site #0070300
City
Tomsk
ZIP/Postal Code
634052
Country
Russian Federation
Facility Name
Merz Investigational Site #0070301
City
Yekaterinburg
ZIP/Postal Code
620149
Country
Russian Federation
Facility Name
Merz Investigational Site #3810001
City
Belgrade
ZIP/Postal Code
11040
Country
Serbia
Facility Name
Merz Investigational Site #3800001
City
Dnipropetrovsk
ZIP/Postal Code
49027
Country
Ukraine
Facility Name
Merz Investigational Site #3800012
City
Ivano-Frankivsk
ZIP/Postal Code
76014
Country
Ukraine
Facility Name
Merz Investigational Site #3800005
City
Kharkiv
ZIP/Postal Code
61068
Country
Ukraine
Facility Name
Merz Investigational Site #3800007
City
Kharkiv
ZIP/Postal Code
61153
Country
Ukraine
Facility Name
Merz Investigational Site #3800013
City
Kherson
ZIP/Postal Code
73010
Country
Ukraine
Facility Name
Merz Investigational site #3800003
City
Odesa
ZIP/Postal Code
65012
Country
Ukraine
Facility Name
Merz Investigational Site #3800009
City
Ternopil
ZIP/Postal Code
46020
Country
Ukraine
Facility Name
Merz Investigational Site #3800011
City
Zaporizhzhya
ZIP/Postal Code
69063
Country
Ukraine

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
34341153
Citation
Berweck S, Bonikowski M, Kim H, Althaus M, Flatau-Baque B, Mueller D, Banach MD. Placebo-Controlled Clinical Trial of IncobotulinumtoxinA for Sialorrhea in Children: SIPEXI. Neurology. 2021 Aug 2;97(14):e1425-36. doi: 10.1212/WNL.0000000000012573. Online ahead of print.
Results Reference
result
PubMed Identifier
36136523
Citation
Berweck S, Banach M, Gaebler-Spira D, Chambers HG, Schroeder AS, Geister TL, Althaus M, Hanschmann A, Vacchelli M, Bonfert MV, Heinen F, Dabrowski E. Safety Profile and Lack of Immunogenicity of IncobotulinumtoxinA in Pediatric Spasticity and Sialorrhea: A Pooled Analysis. Toxins (Basel). 2022 Aug 25;14(9):585. doi: 10.3390/toxins14090585.
Results Reference
derived

Learn more about this trial

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

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