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Effect of Low-Dose Celecoxib on SMN2 in Patients With Spinal Muscular Atrophy (SMA)

Primary Purpose

Spinal Muscular Atrophy (SMA)

Status
Terminated
Phase
Phase 2
Locations
Canada
Study Type
Interventional
Intervention
celecoxib
Sponsored by
Hugh McMillan
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Spinal Muscular Atrophy (SMA)

Eligibility Criteria

2 Years - 80 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Confirmed genetic diagnosis consistent with SMA that can include: SMN1 gene deletions, rearrangements and/or mutations
  2. Sufficient clinical information enabling the patient to be classified as either SMA type II or III. (Patients with SMA type II are defined as having achieved the motor milestone of sitting independently for > 30 seconds but not having been able to stand or walk unsupported. Patients with SMA type III are defined as having achieved the motor milestone of standing or walking independently).
  3. Confirmed genetic test result indicating number of SMN2 gene copies
  4. Age > 2.0 years old at screening
  5. Patients weighing at least 12 kg at screening
  6. Stable dosing (for at least 3 months) of medications that may affect function of muscle, nerve and/or neuromuscular transmission or gene expression (including but not limited to: coenzyme Q10, creatine monohydrate, nutritional supplements, oral salbutamol, valproic acid, sodium phenylbutyrate, hydroxyurea)
  7. Written informed consent obtained from patient and/or parents or legal guardians

Exclusion Criteria:

  1. Clinical presentation and/or genetic testing that is not consistent with SMA type II or III
  2. Inability or unwillingness to swallow celecoxib suspension
  3. Major surgery (scoliosis repair, G-tube insertion) within past 3 months
  4. Known hypersensitivity or allergy to celecoxib (including asthma, urticaria and/or other allergic symptoms resulting from prior celecoxib ingestion) or its excipients, or other NSAIDs (non-steroidal anti-inflammatory drugs) including ASA (Acetylsalicylic Acid)
  5. Known hypersensitivity or allergy to Ora-Blend® or its excipients
  6. Demonstrated allergic-type reaction to sulfonamides
  7. Celecoxib use within 2 weeks prior to screening visit
  8. Known cardiac (ie. uncontrolled heart failure, cerebrovascular bleeding, hypertension requiring the use of anti-hypertensive medication), hepatic (i.e. severe liver impairment or active liver disease), gastrointestinal (i.e. inflammatory bowel disease; active gastric/duodenal/peptic ulcer disease; or active gastrointestinal bleeding), hematologic (ie. thrombocytopenia defined as platelets < 50,000 or hemophilia), respiratory or renal disease(i.e. severe renal impairment defined as creatinine clearance < 30 mL/min) wherein the use of NSAIDs is contraindicated as per Product Monograph dated 03 March 2015.
  9. Concurrent use of medication contraindicated with Celecoxib use (including but not limited to, warfarin, fluconazole, lithium, hydrochlorothiazide)
  10. Female who is pregnant or breast feeding
  11. Female of child-bearing potential who is sexually active and unwilling or unable to use at least one form of highly effective and one effective method of birth control.
  12. Patients participating in any pharmaceutical clinical trial (with active agent) that could impact with the results of this study
  13. Inability or refusal to provide informed consent

Sites / Locations

  • Children's Hospital of Eastern Ontario

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Open-label

Arm Description

All patients will be treated at each dose of oral once daily celecoxib (40, 80 and 160 mcg/kg) for a period of two weeks, for a total of 6 weeks (42 days) of treatment.

Outcomes

Primary Outcome Measures

low-dose oral celecoxib administered to patients with SMA type II and III is associated with an increase in the levels of peripheral leukocyte SMN protein compared to baseline
1) Investigate change in peripheral leukocyte SMN protein levels from baseline at each dose (40 mcg/kg, 80 mcg/kg, and 160 mcg/kg) of celecoxib.

Secondary Outcome Measures

Safety Profile Measured by Adverse Event Frequency,Type and Severity
1) Determine safety profile as measured by number, type and severity of adverse events reported following administration of low dose celecoxib in patients with type II and III SMA
Recruitment Plan Measured by Number of Potentially Eligible Subjects
Assess understanding of recruitment barriers measured by the number of potentially eligible subjects and response to study recruitment phase.
Compliance Measured by Reported Protocol Deviations
Assess adherence to treatment protocol measured by number of reported protocol deviations.
Eligibility Measured by Number of Screen Failures
Assess appropriateness of eligibility criteria based on number of screen failures.
Delivery Time of Shipped Samples Assessed by Viability
Assess feasibility of shipping laboratory samples to outside centre for analysis. This will be reported based on the time to deliver and the resulting viability of the received samples by either pre or post testing or both if appropriate.

Full Information

First Posted
August 9, 2016
Last Updated
October 13, 2020
Sponsor
Hugh McMillan
Collaborators
Families of Spinal Muscular Atrophy, Gwendolyn Strong Foundation
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1. Study Identification

Unique Protocol Identification Number
NCT02876094
Brief Title
Effect of Low-Dose Celecoxib on SMN2 in Patients With Spinal Muscular Atrophy
Acronym
SMA
Official Title
A Pilot, Open-Label, Dose Response Study Investigating the Effect of Low-Dose Celecoxib on SMN2 in Patients With Spinal Muscular Atrophy (SMA)
Study Type
Interventional

2. Study Status

Record Verification Date
October 2020
Overall Recruitment Status
Terminated
Why Stopped
Terminated: Study halted prematurely and will not resume; participants are no longer being examined or receiving intervention
Study Start Date
January 29, 2019 (Actual)
Primary Completion Date
August 6, 2020 (Actual)
Study Completion Date
August 6, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Hugh McMillan
Collaborators
Families of Spinal Muscular Atrophy, Gwendolyn Strong Foundation

4. Oversight

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

5. Study Description

Brief Summary
Several factors make the use of celecoxib in human SMA patients appealing including: 1) low-dosing required for potential therapeutic effect (the corresponding dose in humans is much lower than that commonly used in adults and children with; 2) favourable side effect profile of this drug (particularly at the dosing required); 3) the fact that celecoxib crosses the blood brain barrier and 4) demonstration of efficacy in a genetically and pathophysiologically faithful animal mode. The investigators therefore believe that celecoxib is a promising disease modifying therapy for SMA.
Detailed Description
This is a pilot, open-label, dose-response study in patients with SMA type II or III. All patients will be treated at each dose of once daily celecoxib (40, 80 and 160 mcg/kg) for a period of two weeks, for a total of 6 weeks (42 days) of treatment.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Spinal Muscular Atrophy (SMA)

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
1 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Open-label
Arm Type
Experimental
Arm Description
All patients will be treated at each dose of oral once daily celecoxib (40, 80 and 160 mcg/kg) for a period of two weeks, for a total of 6 weeks (42 days) of treatment.
Intervention Type
Drug
Intervention Name(s)
celecoxib
Other Intervention Name(s)
CeleBREX
Intervention Description
dose-response
Primary Outcome Measure Information:
Title
low-dose oral celecoxib administered to patients with SMA type II and III is associated with an increase in the levels of peripheral leukocyte SMN protein compared to baseline
Description
1) Investigate change in peripheral leukocyte SMN protein levels from baseline at each dose (40 mcg/kg, 80 mcg/kg, and 160 mcg/kg) of celecoxib.
Time Frame
baseline
Secondary Outcome Measure Information:
Title
Safety Profile Measured by Adverse Event Frequency,Type and Severity
Description
1) Determine safety profile as measured by number, type and severity of adverse events reported following administration of low dose celecoxib in patients with type II and III SMA
Time Frame
4 weeks post
Title
Recruitment Plan Measured by Number of Potentially Eligible Subjects
Description
Assess understanding of recruitment barriers measured by the number of potentially eligible subjects and response to study recruitment phase.
Time Frame
4 weeks post
Title
Compliance Measured by Reported Protocol Deviations
Description
Assess adherence to treatment protocol measured by number of reported protocol deviations.
Time Frame
4 weeks post
Title
Eligibility Measured by Number of Screen Failures
Description
Assess appropriateness of eligibility criteria based on number of screen failures.
Time Frame
4 weeks post
Title
Delivery Time of Shipped Samples Assessed by Viability
Description
Assess feasibility of shipping laboratory samples to outside centre for analysis. This will be reported based on the time to deliver and the resulting viability of the received samples by either pre or post testing or both if appropriate.
Time Frame
4 weeks post

10. Eligibility

Sex
All
Minimum Age & Unit of Time
2 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Confirmed genetic diagnosis consistent with SMA that can include: SMN1 gene deletions, rearrangements and/or mutations Sufficient clinical information enabling the patient to be classified as either SMA type II or III. (Patients with SMA type II are defined as having achieved the motor milestone of sitting independently for > 30 seconds but not having been able to stand or walk unsupported. Patients with SMA type III are defined as having achieved the motor milestone of standing or walking independently). Confirmed genetic test result indicating number of SMN2 gene copies Age > 2.0 years old at screening Patients weighing at least 12 kg at screening Stable dosing (for at least 3 months) of medications that may affect function of muscle, nerve and/or neuromuscular transmission or gene expression (including but not limited to: coenzyme Q10, creatine monohydrate, nutritional supplements, oral salbutamol, valproic acid, sodium phenylbutyrate, hydroxyurea) Written informed consent obtained from patient and/or parents or legal guardians Exclusion Criteria: Clinical presentation and/or genetic testing that is not consistent with SMA type II or III Inability or unwillingness to swallow celecoxib suspension Major surgery (scoliosis repair, G-tube insertion) within past 3 months Known hypersensitivity or allergy to celecoxib (including asthma, urticaria and/or other allergic symptoms resulting from prior celecoxib ingestion) or its excipients, or other NSAIDs (non-steroidal anti-inflammatory drugs) including ASA (Acetylsalicylic Acid) Known hypersensitivity or allergy to Ora-Blend® or its excipients Demonstrated allergic-type reaction to sulfonamides Celecoxib use within 2 weeks prior to screening visit Known cardiac (ie. uncontrolled heart failure, cerebrovascular bleeding, hypertension requiring the use of anti-hypertensive medication), hepatic (i.e. severe liver impairment or active liver disease), gastrointestinal (i.e. inflammatory bowel disease; active gastric/duodenal/peptic ulcer disease; or active gastrointestinal bleeding), hematologic (ie. thrombocytopenia defined as platelets < 50,000 or hemophilia), respiratory or renal disease(i.e. severe renal impairment defined as creatinine clearance < 30 mL/min) wherein the use of NSAIDs is contraindicated as per Product Monograph dated 03 March 2015. Concurrent use of medication contraindicated with Celecoxib use (including but not limited to, warfarin, fluconazole, lithium, hydrochlorothiazide) Female who is pregnant or breast feeding Female of child-bearing potential who is sexually active and unwilling or unable to use at least one form of highly effective and one effective method of birth control. Patients participating in any pharmaceutical clinical trial (with active agent) that could impact with the results of this study Inability or refusal to provide informed consent
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Hugh McMillan, MD
Organizational Affiliation
Children's Hospital of Eastern Ontario Research Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
Children's Hospital of Eastern Ontario
City
Ottawa
State/Province
Ontario
ZIP/Postal Code
K1H8L1
Country
Canada

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Results will be submitted for presentation at an international meeting and subsequently submitted for publication in a major international peer-reviewed medical journal.

Learn more about this trial

Effect of Low-Dose Celecoxib on SMN2 in Patients With Spinal Muscular Atrophy

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