## Protocol Section
### Identification Module
**NCT ID:** NCT06430385

**Brief Title:** ATTUNE: A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Intrathecally-Administered ION440 in Participants With Methyl CpG Binding Protein 2 (MECP2) Duplication Syndrome (MDS)

**Official Title:** A Phase 1-2, Double-Blind, Sham-Controlled Multiple Ascending Dose Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Intrathecally-Administered ION440 in Patients With MECP2 Duplication Syndrome

#### Organization Study ID Info
**ID:** ION440-CS1
#### Organization
**Class:** INDUSTRY
**Full Name:** Ionis Pharmaceuticals, Inc.
#### Secondary ID Infos
**ID:** 2023-507192-22
**Type:** EUDRACT_NUMBER
### Status Module
#### Completion Date
**Date:** 2030-04

**Type:** ESTIMATED

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2024-05-28

**Type:** ACTUAL

**Last Update Submit Date:** 2024-05-21

**Overall Status:** NOT_YET_RECRUITING

#### Primary Completion Date
**Date:** 2026-05

**Type:** ESTIMATED

#### Start Date
**Date:** 2024-08

**Type:** ESTIMATED

**Status Verified Date:** 2024-05

#### Study First Post Date
**Date:** 2024-05-28
**Type:** ACTUAL
**Study First Submit Date:** 2024-05-21
**Study First Submit QC Date:** 2024-05-21
### Sponsor Collaborators Module

#### Lead Sponsor

**Class:** INDUSTRY

**Name:** Ionis Pharmaceuticals, Inc.

#### Responsible Party

**Type:** SPONSOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** True

**Oversight Has DMC:** True

### Description Module

**Brief Summary:** The primary purpose of this study is to evaluate the safety and tolerability of ION440.

**Detailed Description:** This is a phase 1-2 randomized, double-blind, sham-controlled, multiple-ascending dose (MAD) study to evaluate ION440 in pediatric and adult participants with MECP2 Duplication Syndrome (MDS) and will be conducted in two parts. During Part 1 (MAD) (36 weeks), participants will be randomized in a 3:1 ratio to receive ION440 or sham. Individuals who complete Part 1 may enter Part 2, an open label long-term extension study (LTE), where they will receive ION440 for up to approximately 156 weeks. Multiple dose cohorts (Dose A, Dose B, and Dose C) will be evaluated in the study.

All dosing cohorts will be further subdivided by age. Sub cohort A will include participants 8 years of age and older and sub cohort B will include participants 2 through 7 years of age. Dosing cohorts will be enrolled sequentially with sub cohort A initiating prior to sub cohort B.

### Conditions Module

**Conditions:**

- Methyl CpG Binding Protein 2 (MECP2) Duplication Syndrome

### Design Module

#### Design Info

**Allocation:** RANDOMIZED

**Intervention Model:** SEQUENTIAL

##### Masking Info

**Masking:** QUADRUPLE

**Who Masked:**

- PARTICIPANT

- CARE_PROVIDER

- INVESTIGATOR

- OUTCOMES_ASSESSOR

**Primary Purpose:** TREATMENT

#### Enrollment Info

**Count:** 48

**Type:** ESTIMATED

**Phases:**

- PHASE1

- PHASE2

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** Participants will receive ION440 intrathecally at Dose A during Part 1/MAD, followed by ION440 Dose A during Part 2/LTE.

**Intervention Names:**

- Drug: ION440

**Label:** Cohort 1: ION440 Dose A

**Type:** EXPERIMENTAL

#### Arm Group 2

**Description:** Participants will receive ION440 intrathecally at Dose B during Part 1/MAD, followed by ION440 Dose B during Part 2/LTE.

**Intervention Names:**

- Drug: ION440

**Label:** Cohort 2: ION440 Dose B

**Type:** EXPERIMENTAL

#### Arm Group 3

**Description:** Participants will receive ION440 intrathecally at Dose C during Part 1/MAD, followed by ION440 Dose C during Part 2/LTE.

**Intervention Names:**

- Drug: ION440

**Label:** Cohort 3: ION440 Dose C

**Type:** EXPERIMENTAL

#### Arm Group 4

**Description:** During the Part 1/MAD period, a lumbar procedure (LP) will be performed at the same frequency as ION440 administration. Participants will not receive ITB injections during this period. It will be followed by the open-label Part 2/LTE period, where participants will receive ION440 at the same dose as their enrolled cohort (e.g. Dose A, Dose B or Dose C).

**Intervention Names:**

- Procedure: Sham procedure

**Label:** Sham Procedure

**Type:** SHAM_COMPARATOR

### Interventions

#### Intervention 1

**Arm Group Labels:**

- Cohort 1: ION440 Dose A

- Cohort 2: ION440 Dose B

- Cohort 3: ION440 Dose C

**Description:** ION440 will be administered by intrathecal bolus (ITB) injection.

**Name:** ION440

**Type:** DRUG

#### Intervention 2

**Arm Group Labels:**

- Sham Procedure

**Description:** An LP will be performed with CSF collection but will not be followed by the administration of study treatment by ITB injection.

**Name:** Sham procedure

**Type:** PROCEDURE

### Outcomes Module

#### Primary Outcomes

**Measure:** Part 1: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)

**Time Frame:** Up to approximately 36 weeks

**Measure:** Part 1: Number of Participants With Clinically Significant Change From Baseline in Vital Signs

**Time Frame:** Baseline up to approximately 36 weeks

**Measure:** Part 1: Number of Participants With Clinically Significant Change From Baseline in Physical and Neurological Examination Findings

**Time Frame:** Baseline up to approximately 36 weeks

**Measure:** Part 1: Number of Participants With Clinically Significant Change from Baseline in Laboratory Assessments

**Time Frame:** Baseline up to approximately 36 weeks

**Measure:** Part 1: Number of Participants With Clinically Significant Change From Baseline in Electrocardiogram (ECG)

**Time Frame:** Baseline up to approximately 36 weeks

**Measure:** Part 2: Number of Participants With TEAEs

**Time Frame:** Up to approximately 192 weeks

**Measure:** Part 2: Number of Participants With Clinically Significant Change From Baseline in Vital Signs

**Time Frame:** Baseline up to approximately 192 weeks

**Measure:** Part 2: Number of Participants With Clinically Significant Change From Baseline in Physical and Neurological Examination Findings

**Time Frame:** Baseline up to approximately 192 weeks

**Measure:** Part 2: Number of Participants With Clinically Significant Change from Baseline in Laboratory Assessments

**Time Frame:** Baseline up to approximately 192 weeks

**Measure:** Part 2: Number of Participants With Clinically Significant Change From Baseline in ECG

**Time Frame:** Baseline up to approximately 192 weeks

#### Secondary Outcomes

**Measure:** Part 1: Maximum Observed Concentration (Cmax) of ION440 in Plasma

**Time Frame:** Pre-dose and at multiple points post-dose up to Week 36

**Measure:** Part 1: Area Under the Concentration-time Curve (AUC) of ION440 in Plasma

**Time Frame:** Pre-dose and at multiple points post-dose up to Week 36

**Measure:** Part 1: Plasma Terminal Elimination Half-life (t½) of ION440

**Time Frame:** Pre-dose and at multiple points post-dose up to Week 36

**Measure:** Part 1: Trough Concentration (Ctrough) of ION440 in Plasma and CSF

**Time Frame:** Pre-dose and at multiple points post-dose up to Week 36

**Measure:** Part 1: Plasma Concentration of ION440

**Time Frame:** Pre-dose and at multiple points post-dose up to Week 36

**Measure:** Part 2: Trough Concentration (Ctrough) of ION440 in Plasma and CSF

**Time Frame:** Up to approximately 192 weeks

### Eligibility Module

**Eligibility Criteria:** Inclusion criteria for Part 1:

1. Males age ≥ 2 years to ≤ 65 years old, depending on specific cohort and group, at the time of informed consent.

   1. Group A: ≥ 8 to ≤ 65 years old
   2. Group B: 2 to 7 years old, inclusive
2. Participant has at least one parent or caregiver ≥ 18 years old capable of providing informed consent (signed and dated), and able to attend all scheduled study visits and provide feedback regarding the participant's symptoms and performance as described in the protocol, and able to comply with all study requirements and activities,
3. Participant has a documented diagnosis of MDS, with genetic confirmation of MECP2 duplication
4. Is currently receiving stable doses of concomitant medications for at least 3 months prior to baseline. If recent changes (\< 3 months stable) in medications, the participant may be allowed per Investigator judgment in consult with Sponsor Medical Monitor.
5. Able to complete all study procedures, measurements and visits and caregiver/participant has adequately supportive psychosocial circumstances, in the opinion of the Investigator.

Exclusion criteria for Part 1:

1. Documented diagnosis of complex MECP2 duplications including terminal duplication and/or translocation or MECP2 triplication OR clinical features associated with complex variant structure including (a) onset of seizures prior to age 5 (for those age 5 and above at signing of ICF), (b) oxygen dependence, (c) microcephaly, IF MECP2 genetic structure information is unavailable.
2. Clinically significant vital sign or ECG abnormality at Screening \[including heart rate (HR) \< 45 beats per minute; systolic blood pressure \< 90 millimeters of mercury (mmHg); confirmed blood pressure readings \> 170/105 mmHg\]
3. Known brain or spinal disease that would interfere with the LP procedure, or CSF circulation or presence of other factors would affect the safety of the LP procedure.
4. Has any concomitant disease or condition or circumstance, or any finding at Screening that, in the opinion of the Investigator, makes the participant unsuitable for enrollment or that could interfere with the conduct of the study or that would pose an unacceptable risk to the participant in this study.
5. Treatment with an investigational drug, biological agent, or device within 30 days of Screening, or 5 half-lives of investigational agent, whichever is longer.
6. Previous treatment with an oligonucleotide (including siRNA) within 4 months of Screening if single dose received, or within 12 months of Screening if multiple doses received (this exclusion does not apply to vaccines - both mRNA and viral vector vaccines are allowed including COVID-19). For centrally administered ASOs, a minimum of 12 months washout is required irrespective of the number of doses received.
7. Currently enrolled in a clinical trial of an investigational agent or device or has used any investigational agent or device within 5 half-lives of investigational agent, whichever is longer.
8. Has a history of gene therapy or cell transplantation or any other experimental brain surgery.
9. Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Baseline (Day 1).
10. Has experienced Status Epilepticus in the past 6 months.

Inclusion criteria for Part 2:

1. Completed ION440-CS1, Part 1/MAD. Completers are defined as participants who received at least one dose of Study Drug and attended all study visits through Follow Up.
2. All inclusion criteria in Part 1/MAD apply (participants will not be required to undergo new Screening bloodwork).

Exclusion criteria for Part 2:

1. Has developed any concomitant disease (e.g., gastrointestinal, renal, hepatic, endocrine, respiratory, or cardiovascular system disease) or condition or circumstance, or any finding during Part 1/MAD that, in the opinion of the Investigator, makes the participant unsuitable for continued treatment (e.g. could interfere with the conduct of the study or that would pose an unacceptable risk to the participant in this study).

**Gender Based:** True

**Gender Description:** Only males are included for this disease condition.

**Maximum Age:** 65 Years

**Minimum Age:** 2 Years

**Sex:** MALE

**Standard Ages:**

- CHILD

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Central Contacts

**Contact 1:**

**Email:** IonisMECP2study@clinicaltrialmedia.com

**Name:** Ionis Pharmaceuticals

**Phone:** (844) 779-1497

**Role:** CONTACT

### IPD Sharing Statement Module

**IPD Sharing:** NO

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000004194

- Term: Disease

- ID: D000010335

- Term: Pathologic Processes

- ID: D000038901

- Term: Mental Retardation, X-Linked

- ID: D000008607

- Term: Intellectual Disability

- ID: D000019954

- Term: Neurobehavioral Manifestations

- ID: D000009461

- Term: Neurologic Manifestations

- ID: D000009422

- Term: Nervous System Diseases

- ID: D000040181

- Term: Genetic Diseases, X-Linked

- ID: D000030342

- Term: Genetic Diseases, Inborn

- ID: D000020271

- Term: Heredodegenerative Disorders, Nervous System

### Condition Browse Module - Browse Branches

- Abbrev: BC23

- Name: Symptoms and General Pathology

- Abbrev: All

- Name: All Conditions

- Abbrev: BC10

- Name: Nervous System Diseases

- Abbrev: BC16

- Name: Diseases and Abnormalities at or Before Birth

- Abbrev: BXM

- Name: Behaviors and Mental Disorders

- Abbrev: Rare

- Name: Rare Diseases

### Condition Browse Module - Browse Leaves

- ID: M16355

- Name: Syndrome

- Relevance: HIGH

- As Found: Syndrome

- ID: M18163

- Name: Rett Syndrome

- Relevance: HIGH

- As Found: Methyl CpG Binding Protein 2

- ID: M11589

- Name: Intellectual Disability

- Relevance: LOW

- As Found: Unknown

- ID: M24774

- Name: Mental Retardation, X-Linked

- Relevance: LOW

- As Found: Unknown

- ID: M21826

- Name: Neurobehavioral Manifestations

- Relevance: LOW

- As Found: Unknown

- ID: M12404

- Name: Neurologic Manifestations

- Relevance: LOW

- As Found: Unknown

- ID: M24877

- Name: Genetic Diseases, X-Linked

- Relevance: LOW

- As Found: Unknown

- ID: M23686

- Name: Genetic Diseases, Inborn

- Relevance: LOW

- As Found: Unknown

- ID: M22092

- Name: Heredodegenerative Disorders, Nervous System

- Relevance: LOW

- As Found: Unknown

- ID: T4987

- Name: Rett Syndrome

- Relevance: HIGH

- As Found: Methyl CpG Binding Protein 2

- ID: T3658

- Name: MECP2 Duplication Syndrome

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000015518

- Term: Rett Syndrome

- ID: D000013577

- Term: Syndrome

### Misc Info Module

- Version Holder: 2024-05-31
