A Study to Evaluate the Safety, Biomarkers, and Efficacy of Tominersen Compared With Placebo in Participants with Prodromal and Early Manifest Huntington’s Disease

Overview

Sponsor-declared trial summary

Key facts

Sponsor

F. Hoffmann-La Roche AG

Participant type

Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

Not possible to specify, Diseases [C] - Nervous System Diseases [C10]

Trial duration

1 Feb 2023 → ongoing

Decision date (initial)

2024-05-22

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

F. Hoffmann-La Roche Ltd

External identifiers

EU CT number

2023-503928-10-00

EudraCT number

2022-001991-32

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Others

To evaluate the safety of tominersen compared with placebo on the basis of incidence and severity of adverse events, with severity determined according to the Adverse Event Severity Grading Scale, change from baseline in clinical laboratory results [cerebrospinal fluid (CSF) white blood cell (WBC) and protein], and safety magnetic resonance imaging (MRI) (DB Period)
To evaluate CSF mutant huntingtin (mHTT) protein levels in response to tominersen compared with placebo at 9 months (DB Period)
To evaluate the efficacy of tominersen compared with placebo on the basis of change from baseline in composite unified huntington's disease rating scale (cUHDRS) (non-U.S.) and total functional capacity (TFC) (U.S.) at 16 months (DB Period)
To evaluate the safety of long-term tominersen administration on the basis incidence and severity of adverse events, with severity determined according to the Adverse Event Severity Grading Scale, Change over time in clinical laboratory results (CSF, WBC and protein), and safety MRI (OLE Period)

Secondary objectives 4

1. To evaluate the safety of tominersen compared with placebo on the basis of change from baseline in vital signs, electrocardiogram (ECG) parameters, plasma clinical laboratory results, montreal cognitive assessment (MoCA), and proportion of participants with suicidal ideation or behavior as assessed by columbia-suicide severity rating scale (C-SSRS) score at each visit (DB Period) To evaluate the safety of long-term tominersen on the basis of change over time in vital signs, electrocardiogram (ECG) parameters, plasma clinical laboratory results, montreal cognitive assessment (MoCA), and proportion of participants with suicidal ideation or behavior as assessed by columbia-suicide severity rating scale (C-SSRS) score at each visit (OLE Period)
2. To evaluate the efficacy of tominersen compared with placebo on the basis of change from baseline at 16 months for the assessments of TFC (non-U.S.)/cUHDRS (U.S.), symbol digit modalities test (SDMT) stroop word reading (SWR) and total motor score (TMS) (DB Period) To evaluate the efficacy of long-term tominersen on the basis of change over time for the assessments of cUHDRS, TFC, symbol digit modalities test (SDMT) stroop word reading (SWR) and total motor score (TMS) (OLE Period)
3. To evaluate change from baseline in CSF neurofilament light chain (NfL) in response to tominersen compared with placebo at 16 months (DB Period)
4. To evaluate the immune response to tominersen (DB Period) To evaluate the immune response to long-term tominersen administration (OLE Period)

Conditions and MedDRA coding

Prodromal and Early Manifest Huntington’s Disease

Study design 1 period

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-002546-PIP01-19

Plan to share IPD

No

IPD plan description

NA

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. Huntington’s disease (HD) gene expansion mutation carrier status with a CAP score of 400-500 inclusive
2. Either: Prodromal HD (defined as DCL 2 to 3, Independence Scale (IS) ⩾70, and ⩾TFC8); or Early manifest HD (defined as DCL 4, Independence Scale (IS) ⩾70, and ⩾TFC8)
3. Estimated glomerular filtration rate ≥ 60 mL/min/1.73 m2 in at least one out of two maximum screening samples
4. Total body weight > 40 kg and a body mass index within the range of 18-32 kg/m2
5. Age 25- 50 years, inclusive, at the time of signing the Informed Consent Form
6. Study Companion

Exclusion criteria 6

1. History of attempted suicide or suicidal ideation with plan that required hospital visit and/or change in level of care within 12 months prior to screening
2. Current or previous use of an ASO (including small interfering RNA) or any HTT lowering therapy (including tominersen)
3. Anti-platelet or anticoagulant therapy
4. Pregnancy or breastfeeding, or intention of becoming pregnant during the study or within 5 months after the final dose of study drug
5. History of gene therapy, cell transplantation, or brain surgery
6. Hydrocephalus

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 8

1. Incidence and severity of adverse events, with severity determined according to the Adverse Event Severity Grading Scale (DB Period)
2. Change from baseline in clinical laboratory results (CSF WBC and protein) (DB Period)
3. Safety MRI (DB Period)
4. Percentage change from baseline in geometric means of CSF mHTT protein levels at Month 9 (DB Period)
5. Change from baseline in cUHDRS (non-U.S.) and TFC (U.S.) at 16 months (DB Period)
6. Incidence and severity of adverse events, with severity determined according to the Adverse Event Severity Grading Scale (OLE Period)
7. Change over time in clinical laboratory results (CSF, WBC, and protein) (OLE period)
8. Safety MRI (OLE period)

Secondary endpoints 16

1. Change from baseline in vital signs (DB period)
2. Change from baseline in ECG parameters (DB period)
3. Change from baseline in plasma clinical laboratory results (DB period)
4. Change from baseline in MoCA (DB period)
5. Proportion of participants with suicidal ideation or behavior as assessed by C-SSRS score at each visit, including detailed focus on any individual cases identified as having severe ideation or behavior during the study conduct (DB period)
6. Change from baseline at 16 months for the assessments of TFC (non-U.S.)/cUHDRS (U.S.), SDMT, TMS, and SWR (DB period)
7. Change from baseline in CSF NfL levels at 16 months (DB period)
8. Incidence of anti-drug antibodies (ADAs) at specified timepoints relative to the prevalence of ADAs at baseline (DB period)
9. Titers will be determined if ADAs are identified (DB period)
10. Change over time in cUHDRS, TFC, SDMT, TMS, SWR (OLE period)
11. Change over time in vital signs (OLE period)
12. Change over time in ECG parameters (OLE period)
13. Change over time in plasma clinical laboratory results (OLE period)
14. Change over time in MoCA (OLE period)
15. Proportion of participants with suicidal ideation or behavior as assessed by C-SSRS score at each visit, including detailed focus on any individual cases identified as having severe ideation or behavior during the study conduct (OLE period)
16. Incidence of ADAs at specified timepoints (OLE period)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

F. Hoffmann-La Roche AG

Sponsor organisation

F. Hoffmann-La Roche AG

Address

Grenzacherstrasse 124

City

Basel

Postcode

4058

Country

Switzerland

Scientific contact point

Organisation

F. Hoffmann-La Roche AG

Contact name

Trial Information System - TISL

Public contact point

Organisation

F. Hoffmann-La Roche AG

Contact name

Trial Information System - TISL

Third parties 12

Locations

8 EU/EEA countries · 32 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Serious breaches 2 · Art. 52 CTR

Urgent safety measures 1 · Art. 54 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 103 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

13 submissions — initial application plus substantial / non-substantial modifications