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

• ClinicalTrials.gov Identifier: NCT02312011
• Recruitment Status: Completed
• First Posted: December 9, 2014
• Last Update Posted: December 6, 2022
• Sponsor: Ionis Pharmaceuticals, Inc.
• Information provided by (Responsible Party): Ionis Pharmaceuticals, Inc.

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.

Condition or disease	Intervention/treatment	Phase
Myotonic Dystrophy Type 1	Drug: IONIS-DMPKRx; Drug: Placebo	Phase 1; Phase 2

Detailed Description:

This is a Phase 1/2a multicenter, blinded, placebo-controlled study of ISIS-DMPK Rx in adult patients with DM1.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 48 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• 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 Start Date: December 2014
• Actual Primary Completion Date: July 2016
• Actual Study Completion Date: August 2016

Arms and Interventions

Arm	Intervention/treatment
Experimental: IONIS-DMPKRx; 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.	Drug: IONIS-DMPKRx; Drug; Other Name: ISIS 598769
Placebo Comparator: Placebo; A placebo is administered subcutaneously over the course of 6 weeks. A placebo is administered subcutaneously over the course of 12 weeks.	Drug: Placebo; Placebo

Outcome Measures

Primary Outcome Measures :

1. Safety (The number of participants with adverse events) [ Time Frame: Participants will be followed for the duration of the study; an expected 24 - 32 weeks ]
   The number of participants with adverse events
2. Tolerability (The number of participants with adverse events) [ Time Frame: Participants will be followed for the duration of the study; an expected 24 -32 weeks ]
   The number of participants with adverse events

Secondary Outcome Measures :

1. Plasma Pharmacokinetics (Cmax, Tmax) [ Time Frame: Plasma at 0.5, 1, 1.5, 2, 4, 6, 8, 12 and 24 hours after dosing. ]
   • 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)
2. Urine Pharmacokinetics (Amount of drug excreted in the urine) [ Time Frame: 0-24 hours post-dosing ]
   Amount of drug excreted in the urine

Eligibility Criteria

• Ages Eligible for Study: 20 Years to 55 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, California

Stanford University Medical Center

Stanford, California, United States, 94305

United States, Florida

University of Florida

Gainesville, Florida, United States, 32610

United States, Kansas

University of Kansas Medical Center

Kansas City, Kansas, United States, 66103

United States, Maryland

Kennedy Krieger Institute

Baltimore, Maryland, United States, 21205

United States, New York

University of Rochester

Rochester, New York, United States, 14642

United States, Ohio

The Ohio State University

Columbus, Ohio, United States, 43221

United States, Texas

Houston Methodist

Houston, Texas, United States, 77030

United States, Utah

University of Utah

Salt Lake City, Utah, United States, 84132

Sponsors and Collaborators

Ionis Pharmaceuticals, Inc.

More Information

• Responsible Party: Ionis Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT02312011
• Other Study ID Numbers: ISIS 598769-CS2
• First Posted: December 9, 2014
• Last Update Posted: December 6, 2022
• Last Verified: December 2022

Keywords provided by Ionis Pharmaceuticals, Inc.:

Myotonic Dystrophy; DM1; Adult onset; Neuromuscular Disease; DMPKRx

Additional relevant MeSH terms:

Myotonic Dystrophy; Muscular Dystrophies; Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Diseases; Myotonic Disorders; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Nervous System Diseases; Neuromuscular Diseases; Genetic Diseases, Inborn