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A Safety andTolerability Study of Multiple Doses of ISIS-DMPKRx in Adults With Myotonic Dystrophy Type 1

Primary Purpose

Myotonic Dystrophy Type 1

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
IONIS-DMPKRx
Placebo
Sponsored by
Ionis Pharmaceuticals, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Myotonic Dystrophy Type 1 focused on measuring Myotonic Dystrophy, DM1, Adult onset, Neuromuscular Disease, DMPKRx

Eligibility Criteria

20 Years - 55 Years (Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Must have given written informed consent (signed and dated) and any authorizations required by local law and be able to comply with all study requirements
  2. Males or females aged 20 to 55 years old at the time of informed consent
  3. Satisfy the following:

    1. Females: non-pregnant and non-lactating, surgically sterile, post menopausal, abstinent, or if engaged in sexual relations of child-bearing potential, subject is using an acceptable contraceptive method from the time of signing the informed consent until at least 14 weeks after the last dose of Study Drug.
    2. Males: surgically sterile, abstinent or if engaged in sexual relations with a female of child-bearing potential, the subject must be using an acceptable contraceptive method from the time of signing the informed consent form until at least 14 weeks after the last dose of Study Drug.
  4. BMI <35.0 kg/m2
  5. Genetic confirmation of DM1 with DMPK CTG repeat length ≥ 100
  6. Onset of DM1 symptoms after the age of 12
  7. Clinically apparent myotonia equivalent to hand opening time of at least 2 seconds, in the opinion of the Investigator
  8. Ambulatory (orthoses allowed, canes and walkers not allowed) and able to walk at least 25 meters at screening

Exclusion Criteria:

  1. Clinically significant abnormalities in medical history (e.g., previous acute coronary syndrome within 6 months of screening, major surgery within 3 months of screening) or physical examination
  2. Clinically significant abnormalities in screening laboratory values that would render the subject unsuitable for inclusion
  3. Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Study Day 1
  4. Unwilling or unable to comply with study procedures (e.g., muscle biopsies), including follow-up, as specified by this protocol, or unwillingness to cooperate fully with the Investigator
  5. Known history of or previous positive test for human immunodeficiency virus (HIV), hepatitis C, or chronic hepatitis B
  6. Active malignancy or history within last 5 years, except for basal or squamous cell carcinoma of the skin, carcinoma in situ of the cervix that has been successfully treated, or pilomatricoma
  7. Treatment with another investigational drug, biologic agent, or device within one month of screening, or 5 half-lives of investigational agent, whichever is longer; any history of previous treatment with an oligonucleotide (including siRNA)
  8. Recent history of or current drug or alcohol abuse
  9. History of bleeding tendency or ongoing oral anticoagulation
  10. Developmental delay, intellectual disability, or significant behavioral neuropsychiatric manifestations
  11. Thyroid dysfunction that is untreated (if on thyroid hormone replacement therapy, need to have adequate and stable replacement over the previous 6 months)
  12. Implanted device for the treatment of cardiac problems (i.e., pacemaker or defibrillator)
  13. Clinically significant abnormal ECG or echocardiogram, or significant symptoms of cardiac dysfunction at Screening
  14. Have a seizure disorder
  15. If being treated with testosterone, on a stable replacement dose (i.e., for hypogonadism)
  16. Treatment with corticosteroids within 8 weeks prior to the first dose of Study Drug
  17. History of hypersensitivity to local anesthetics to be used in the biopsy procedure or components thereof
  18. Treatment with anti-myotonia medication within 30 days prior to screening. May include, but not be limited to: Phenytoin, Carbamazepine, Procainamide, Disopyramide, Nifedipine, Acetazolamide, Clomipramine, Imipramine, Amytriptiline, Taurine, Quinine, Mexiletine
  19. Have any condition, which, in the opinion of the investigator would make the subject unsuitable for inclusion, or could interfere with the subject participating in or completing the study

Sites / Locations

  • Stanford University Medical Center
  • University of Florida
  • University of Kansas Medical Center
  • Kennedy Krieger Institute
  • University of Rochester
  • The Ohio State University
  • Houston Methodist
  • University of Utah

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

IONIS-DMPKRx

Placebo

Arm Description

IONIS DMPKRx is administered subcutaneously over the course of 6 weeks for dose levels 1, 2, 3, 4, and 5. IONIS DMPKRx is administered subcutaneously over the course of 12 weeks for dose levels 4 or 5.

A placebo is administered subcutaneously over the course of 6 weeks. A placebo is administered subcutaneously over the course of 12 weeks.

Outcomes

Primary Outcome Measures

Safety (The number of participants with adverse events)
The number of participants with adverse events
Tolerability (The number of participants with adverse events)
The number of participants with adverse events

Secondary Outcome Measures

Plasma Pharmacokinetics (Cmax, Tmax)
the maximal observed plasma drug concentration (Cmax) the time to reach Cmax (Tmax) the area under the plasma concentration time curve from the time of the subcutaneous dose to the last collected sample (24 hours after dosing)
Urine Pharmacokinetics (Amount of drug excreted in the urine)
Amount of drug excreted in the urine

Full Information

First Posted
December 4, 2014
Last Updated
December 1, 2022
Sponsor
Ionis Pharmaceuticals, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT02312011
Brief Title
A Safety andTolerability Study of Multiple Doses of ISIS-DMPKRx in Adults With Myotonic Dystrophy Type 1
Official Title
A Phase 1/2a Blinded, Placebo-Controlled Study to Assess the Safety, Tolerability, and Dose-range Finding of Multiple Ascending Doses of ISIS 598769 Administered Subcutaneously to Adult Patients With Myotonic Dystrophy Type 1
Study Type
Interventional

2. Study Status

Record Verification Date
December 2022
Overall Recruitment Status
Completed
Study Start Date
December 2014 (undefined)
Primary Completion Date
July 2016 (Actual)
Study Completion Date
August 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Ionis Pharmaceuticals, Inc.

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
This study will test the safety, tolerability, and pharmacokinetics of multiple escalating doses of ISIS-DMPKRx administered subcutaneously to adult patients with DM1.
Detailed Description
This is a Phase 1/2a multicenter, blinded, placebo-controlled study of ISIS-DMPK Rx in adult patients with DM1.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Myotonic Dystrophy Type 1
Keywords
Myotonic Dystrophy, DM1, Adult onset, Neuromuscular Disease, DMPKRx

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
48 (Actual)

8. Arms, Groups, and Interventions

Arm Title
IONIS-DMPKRx
Arm Type
Experimental
Arm Description
IONIS DMPKRx is administered subcutaneously over the course of 6 weeks for dose levels 1, 2, 3, 4, and 5. IONIS DMPKRx is administered subcutaneously over the course of 12 weeks for dose levels 4 or 5.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
A placebo is administered subcutaneously over the course of 6 weeks. A placebo is administered subcutaneously over the course of 12 weeks.
Intervention Type
Drug
Intervention Name(s)
IONIS-DMPKRx
Other Intervention Name(s)
ISIS 598769
Intervention Description
Drug
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo
Primary Outcome Measure Information:
Title
Safety (The number of participants with adverse events)
Description
The number of participants with adverse events
Time Frame
Participants will be followed for the duration of the study; an expected 24 - 32 weeks
Title
Tolerability (The number of participants with adverse events)
Description
The number of participants with adverse events
Time Frame
Participants will be followed for the duration of the study; an expected 24 -32 weeks
Secondary Outcome Measure Information:
Title
Plasma Pharmacokinetics (Cmax, Tmax)
Description
the maximal observed plasma drug concentration (Cmax) the time to reach Cmax (Tmax) the area under the plasma concentration time curve from the time of the subcutaneous dose to the last collected sample (24 hours after dosing)
Time Frame
Plasma at 0.5, 1, 1.5, 2, 4, 6, 8, 12 and 24 hours after dosing.
Title
Urine Pharmacokinetics (Amount of drug excreted in the urine)
Description
Amount of drug excreted in the urine
Time Frame
0-24 hours post-dosing

10. Eligibility

Sex
All
Minimum Age & Unit of Time
20 Years
Maximum Age & Unit of Time
55 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Must have given written informed consent (signed and dated) and any authorizations required by local law and be able to comply with all study requirements Males or females aged 20 to 55 years old at the time of informed consent Satisfy the following: Females: non-pregnant and non-lactating, surgically sterile, post menopausal, abstinent, or if engaged in sexual relations of child-bearing potential, subject is using an acceptable contraceptive method from the time of signing the informed consent until at least 14 weeks after the last dose of Study Drug. Males: surgically sterile, abstinent or if engaged in sexual relations with a female of child-bearing potential, the subject must be using an acceptable contraceptive method from the time of signing the informed consent form until at least 14 weeks after the last dose of Study Drug. BMI <35.0 kg/m2 Genetic confirmation of DM1 with DMPK CTG repeat length ≥ 100 Onset of DM1 symptoms after the age of 12 Clinically apparent myotonia equivalent to hand opening time of at least 2 seconds, in the opinion of the Investigator Ambulatory (orthoses allowed, canes and walkers not allowed) and able to walk at least 25 meters at screening Exclusion Criteria: Clinically significant abnormalities in medical history (e.g., previous acute coronary syndrome within 6 months of screening, major surgery within 3 months of screening) or physical examination Clinically significant abnormalities in screening laboratory values that would render the subject unsuitable for inclusion Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Study Day 1 Unwilling or unable to comply with study procedures (e.g., muscle biopsies), including follow-up, as specified by this protocol, or unwillingness to cooperate fully with the Investigator Known history of or previous positive test for human immunodeficiency virus (HIV), hepatitis C, or chronic hepatitis B Active malignancy or history within last 5 years, except for basal or squamous cell carcinoma of the skin, carcinoma in situ of the cervix that has been successfully treated, or pilomatricoma Treatment with another investigational drug, biologic agent, or device within one month of screening, or 5 half-lives of investigational agent, whichever is longer; any history of previous treatment with an oligonucleotide (including siRNA) Recent history of or current drug or alcohol abuse History of bleeding tendency or ongoing oral anticoagulation Developmental delay, intellectual disability, or significant behavioral neuropsychiatric manifestations Thyroid dysfunction that is untreated (if on thyroid hormone replacement therapy, need to have adequate and stable replacement over the previous 6 months) Implanted device for the treatment of cardiac problems (i.e., pacemaker or defibrillator) Clinically significant abnormal ECG or echocardiogram, or significant symptoms of cardiac dysfunction at Screening Have a seizure disorder If being treated with testosterone, on a stable replacement dose (i.e., for hypogonadism) Treatment with corticosteroids within 8 weeks prior to the first dose of Study Drug History of hypersensitivity to local anesthetics to be used in the biopsy procedure or components thereof Treatment with anti-myotonia medication within 30 days prior to screening. May include, but not be limited to: Phenytoin, Carbamazepine, Procainamide, Disopyramide, Nifedipine, Acetazolamide, Clomipramine, Imipramine, Amytriptiline, Taurine, Quinine, Mexiletine Have any condition, which, in the opinion of the investigator would make the subject unsuitable for inclusion, or could interfere with the subject participating in or completing the study
Facility Information:
Facility Name
Stanford University Medical Center
City
Stanford
State/Province
California
ZIP/Postal Code
94305
Country
United States
Facility Name
University of Florida
City
Gainesville
State/Province
Florida
ZIP/Postal Code
32610
Country
United States
Facility Name
University of Kansas Medical Center
City
Kansas City
State/Province
Kansas
ZIP/Postal Code
66103
Country
United States
Facility Name
Kennedy Krieger Institute
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21205
Country
United States
Facility Name
University of Rochester
City
Rochester
State/Province
New York
ZIP/Postal Code
14642
Country
United States
Facility Name
The Ohio State University
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43221
Country
United States
Facility Name
Houston Methodist
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
University of Utah
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84132
Country
United States

12. IPD Sharing Statement

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A Safety andTolerability Study of Multiple Doses of ISIS-DMPKRx in Adults With Myotonic Dystrophy Type 1

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