A study to evaluate the effect of SAGE-718 on cognitive function in participants with Huntington's Disease

ISRCTN	ISRCTN17896603
DOI	https://doi.org/10.1186/ISRCTN17896603
EudraCT/CTIS number	2021-005577-16
IRAS number	1004868
ClinicalTrials.gov number	NCT05107128
Secondary identifying numbers	718-CIH-201, IRAS 1004868, CPMS 51899

Submission date: 12/02/2022
Registration date: 16/05/2022
Last edited: 31/01/2025

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Nervous System Diseases

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Record updated in last year

Plain English summary of protocol

Background and study aims:
Huntington’s disease is a rare, inherited disease causing degeneration of the nerve cells in the brain, leading to gradual impairment in movement, learning abilities, and behavior.
The DIMENSION Study is evaluating the safety and effects of an experimental oral drug, SAGE-718, in adults with early Huntington’s disease (HD). This drug is being tested to see if it can specifically target cognitive symptoms associated with HD.

Who can participate?
Adults aged 25 to 65 years, with Huntington’s disease.
What does the study involve? (what interventions will be compared, will all participants receive the same treatment, what measurements will be taken)
The study lasts up to 20 weeks and includes 9 visits to the study office. The study consists of the following parts: -

a. A screening period of 28 days wherein tests will be done to check if participants are eligible to take part in the study.
b. The treatment period of 84 days wherein participants will be randomly divided into 2 groups to receive either SAGE-718 or placebo, by mouth.
c. A follow-up period of 28 days wherein participants will return to the clinic for check-up visits on Day 98 and Day 112 to help collect continued safety and effectiveness data.

What are the possible benefits and risks of participating?
Benefits:
Based on standardized interviews conducted by Sage, pre-manifest and early manifest HD patients are at high risk of losing employment, their ability to drive and to maintain financial security. In these interviews, care partners observed changes in functioning, and reported that they were beginning to assume some financial or home responsibilities that they previously held by the patient.
SAGE-718 may work to restore aberrant N-methyl-D-aspartate (NMDA) receptor activity in patients with early HD and thereby help to ameliorate cognitive deficits seen in these patients.
Risks:
• The most frequently reported side effects seen after study treatment with SAGE-718 were: Dizziness, Headache, Nausea, Vomiting, Upper respiratory tract infection (common cold), Orthostatic hypotension (drop in blood pressure when standing from laying down), Euphoric mood (feelings of physical and emotional well-being, which become excessive, all consuming, and interfere with daily living), Increased levels of alanine aminotransferase (a liver function test).
• Most side effects were reported as mild or moderate in intensity and got better or went away without stopping study treatment with SAGE-718.
• There was no selective distribution or retention of radioactive SAGE-718 to pigmented tissues and no quantifiable concentration of radioactivity was observed in the eye lens in Long Evans rats, implying that potential risk of phototoxicity is low.

Where is the study run from?
Sage Therapeutics, Inc (USA)

When is the study starting and how long is it expected to run for?
May 2021 to October 2024

Who is funding the study?
Sage Therapeutics, Inc (USA)

Who is the main contact?
Amy Bullock, PhD; amy.bullock@sagerx.com

Contact information

Dr Edward Hugh Galbraith Rickards
Principal Investigator

25 Vincent Drive
Edgaston
Birmingham
B15 2FG
United Kingdom

Phone	+44 121 301 2290
Email	hugh.rickards@nhs.net

Dr Amy Bullock
Scientific

55 Cambridge Parkway
Cambridge
MA 02142
United States of America

Phone	+1 619-949-5151
Email	amy.bullock@sagerx.com

Study information

Study design	Interventional double-blind randomized placebo-controlled trial
Primary study design	Interventional
Secondary study design	Randomised controlled trial
Study setting(s)	Other
Study type	Treatment
Participant information sheet	No participant information sheet available
Scientific title	A randomized, placebo-controlled, double-blind study to evaluate the effect of SAGE-718 on cognitive function in participants with Huntington's Disease
Study acronym	DIMENSION
Study objectives	Current study hypothesis as of 31/01/2025: - To evaluate the effect of SAGE-718 on cognitive performance in participants with HD - To evaluate the effect of SAGE-718 on cognition and daily function in participants with HD. - To evaluate the safety and tolerability of SAGE-718 oral capsule in participants with HD. _____ Previous study hypothesis: - To evaluate the effect of SAGE-718 on cognitive performance in participants with HD - To evaluate the effect of SAGE-718 on daily function in participants with HD. - To evaluate the safety and tolerability of SAGE-718 oral capsule in participants with HD.
Ethics approval(s)	Approved 05/05/2022, London-Riverside Research Ethics Committee (Temple Quay House, 2 The Square, Bristol Research Ethics Committee Centre, Bristol, BS1 6PN, UK; +44(0)207 104 8150; riverside.rec@hra.nhs.uk), ref: 22/LO/0177
Health condition(s) or problem(s) studied	Huntington's disease
Intervention	Current interventions as of 25/10/2022: The intervention model is parallel assignment with two arms. Eligible participants will be randomized 1:1 to receive either SAGE-718 (oral softgel lipid capsules) or placebo (SAGE-718-matching oral softgel lipid capsules) for 84 days. After completing the treatment period, participants will return to the clinic for follow-up visits at on Day 98 and Day 112 to collect continued safety and efficacy data. Participants are randomized via an IRT system. _____ Previous interventions: The intervention model is parallel assignment with two arms. Eligible participants will be randomized 1:1 to receive either SAGE-718 (oral capsules) or placebo (SAGE-718-matching oral capsules) for 84 days. After completing the treatment period, participants will return to the clinic for follow-up visits at on Day 98 and Day 112 to collect continued safety and efficacy data. Subjects are randomized via an IRT system.
Intervention type	Drug
Pharmaceutical study type(s)
Phase	Phase II
Drug / device / biological / vaccine name(s)	SAGE-718
Primary outcome measure	Current primary outcome measure as of 31/01/2025: Change from baseline to day 84 in the cognitive function assessed using the Symbol Digit Modalities Test (SDMT) _____ Previous primary outcome measure: Change from baseline to day 84 in the cognitive function assessed using Huntington's Disease Cognitive Assessment Battery (HD-CAB) Composite Score
Secondary outcome measures	Current secondary outcome measures as of 31/01/2025: 1. Change from baseline to day 84 in the functional capacity assessed using Unified Huntington's Disease Rating Scale (UHDRS) - Independence Scale 2. Change from baseline to day 84 in the cognitive function assessed using the Trail Making Test Part B 3. Change from baseline to day 84 in the cognitive function assessed using the One Touch Stockings of Cambridge (OTS) 4. Change from baseline to day 84 in the motor function assessed using the Paced Tapping Test (PTAP) 5. Change from baseline to day 84 in the functioning difficulty assessed using the Huntington’s Disease Everyday Functioning (Hi-DEF) Home subdomain score 6. Change from baseline to day 84 in the cognitive function assessed using the Clinical Global Impression – Severity (CGI-S) Cognitive Status subdomain score 7. Percentage of Participants with Treatment-emergent Adverse Events (TEAEs) up to approximately 112 days _____ Previous secondary outcome measures: 1. Change from baseline to day 84 in the functional capacity assessed using Unified Huntington's Disease Rating Scale (UHDRS) - Independence Scale 2. Change from baseline to day 84 in the motor function assessed using UHDRS - Total Motor Score (TMS) 3. Percentage of Participants with Treatment-emergent Adverse Events (TEAEs) up to approximately 112 days
Overall study start date	26/05/2021
Completion date	03/10/2024

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	25 Years
Upper age limit	65 Years
Sex	Both
Target number of participants	178
Total final enrolment	189
Key inclusion criteria	Current inclusion criteria as of 31/01/2025: 1. Meet all the following criteria for HD at Screening (Days -28 to -2): 1.1. Genetically confirmed disease with huntingtin gene CAG expansion ≥36. 1.2. At Screening, UHDRS-Total Functional Capacity (TFC) score >6 and <13 suggesting no more than a moderate level of functional impairment. 1.3. No features of juvenile HD. 2. Score of 15 to 25 (inclusive) on the Montreal Cognitive Assessment (MoCA) at screening indicating the presence of cognitive impairment. 3. Be willing to invite a study partner, if available, who is reliable, competent, and at least 18 years of age to participate in the study. 4. Be ambulatory (use of assistance devices such as a walker or cane is acceptable as is occasional use of wheelchair, as judged by the investigator. Individuals requiring a wheelchair on a regular basis are excluded), able to travel to the study center, and, as judged by the investigator, is likely to be able to continue to travel to the study center to complete study visits for the duration of the study. 5. Completion of HD-CAB Trail Making-B Test in <240 seconds at Screening (Days -28 to -2). _____ Previous inclusion criteria as of 20/05/2024: 1. Meet all the following criteria for HD at Screening (Days -28 to -2): 1.1. Genetically confirmed disease with huntingtin gene CAG expansion ≥36. 1.2. At Screening, UHDRS-Total Functional Capacity (TFC) score >6 and <13 suggesting no more than a moderate level of functional impairment. 1.3. No features of juvenile HD. 2. Score of 15 to 25 (inclusive) on the Montreal Cognitive Assessment (MoCA) at screening indicating the presence of cognitive impairment. 3. Be willing to invite a study partner, if available, who is reliable, competent, and at least 18 years of age to participate in the study. 4. Be ambulatory (use of assistance devices such as a walker or cane is acceptable as is occasional use of wheelchair, as judged by the investigator. Individuals requiring a wheelchair on a regular basis are excluded), able to travel to the study center, and, as judged by the investigator, is likely to be able to continue to travel to the study center to complete study visits for the duration of the study. _____ Previous inclusion criteria as of 25/10/2022: 1. Meet all the following criteria for HD: 1.1. Genetically confirmed disease with huntingtin gene CAG expansion ≥36. 1.2. UHDRS-Total Functional Capacity (TFC) score >6 and <13. 1.3. No features of juvenile HD. 2. Score <26 on the Montreal Cognitive Assessment (MoCA) at screening. 3. Be willing to invite a study partner, if available, who is reliable, competent, and at least 18 years of age to participate in the study. 4. Be ambulatory (use of assistance devices such as a walker or cane is acceptable as is occasional use of wheelchair, as judged by the investigator. Individuals requiring a wheelchair on a regular basis are excluded), able to travel to the study center, and, as judged by the investigator, is likely to be able to continue to travel to the study center to complete study visits for the duration of the study. _____ Previous inclusion criteria: 1. Meet all the following criteria for HD: 1.1. Genetically confirmed disease with huntingtin gene CAG expansion ≥36. 1.2. UHDRS-Total Functional Capacity (TFC) score >6 and <13. 1.3. No features of juvenile HD. 2. Score <26 on the Montreal Cognitive Assessment (MoCA) at screening. 3. Be willing to invite a study partner, if available, who is reliable, competent, and at least 18 years of age to participate in the study. 4. Be ambulatory (use of assistance devices such as a walker or cane is acceptable; individuals requiring a wheelchair are excluded), able to travel to the study center, and, as judged by the investigator, is likely to be able to continue to travel to the study center to complete study visits for the duration of the study.
Key exclusion criteria	Current exclusion criteria as of 20/05/2024: 1. Have participated in a previous clinical study of SAGE-718, have previous exposure to gene therapy or have participated in any HD investigational drug, biologic, or device trial within 180 days or a non-HD drug, biologic, or device trial within 30 days or 5 half-lives (whichever is longer) (Note: Participants with confirmation of enrollment in the placebo arm of these trials would not be excluded.) 2. Have a diagnosis of an ongoing neurodegenerative condition other than HD, including but not limited to, Alzheimer's Disease, vascular dementia, dementia with Lewy bodies, or Parkinson's Disease _____ Previous exclusion criteria as of 25/10/2022: 1. Have participated in a previous clinical study of SAGE-718, have participated in a previous gene therapy study, or have participated in any other drug, biologic, or device trial within 30 days or 5 half-lives (whichever is longer), unless the participant participated solely in the placebo arm of the study. Additionally, participants who have received treatment with antisense oligonucleotides (ASOs) or a messenger ribonucleic acid (mRNA) splicing modifier will be excluded. 2. Have a diagnosis of an ongoing neurodegenerative condition other than HD, including but not limited to, Alzheimer's Disease, vascular dementia, dementia with Lewy bodies, or Parkinson's Disease _____ Previous exclusion criteria: 1. Have participated in a previous clinical study of SAGE-718, have participated in a previous gene therapy study, or have participated in any other drug, biologic, or device trial within 180 days or 5 half-lives (whichever is longer), unless the patient participated solely in the placebo arm of the study. 2. Have a diagnosis of an ongoing neurodegenerative condition other than HD, including but not limited to, Alzheimer's Disease, vascular dementia, dementia with Lewy bodies, or Parkinson's Disease.
Date of first enrolment	05/11/2021
Date of final enrolment	11/06/2024

Locations

Countries of recruitment

Australia
Canada
England
Scotland
United Kingdom
United States of America

Study participating centres

Birmingham and Solihull Mental Health NHS Foundation Trust

Unit 1
50 Summer Hill Road
Birmingham
B15 2FG
United Kingdom

Re-Cognition Health

Unit 2
5 Research Way
Plymouth
PL6 8BT
United Kingdom

Unit 3

Aberdeen
AB25 2ZA
United Kingdom

Unit 4

Cardiff
CF10 3AX
United Kingdom

Unit 5

Leeds
LS1 3X
United Kingdom

Unit 6

Leeds
LS7 4SA
United Kingdom

Unit 7

Newcastle Upon Tyne
NE6 4QD
United Kingdom

Unit 8

Southampton
SO16 6YD
United Kingdom

Unit 9

Tooting
London
SW17 0QT
United Kingdom

Sponsor information

Sage Therapeutics, Inc.
Industry

55 Cambridge Parkway
Cambridge
MA 02142
United States of America

Phone	+1 619-949-5151
Email	amy.bullock@sagerx.com

Funders

Funder type

Industry

Sage Therapeutics, Inc

No information available

Results and Publications

Intention to publish date
Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Not expected to be made available
Publication and dissemination plan
IPD sharing plan	The datasets generated during and/or analysed during the current study are not expected to be made available due to participant-level data not being a regulatory requirement.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
HRA research summary			28/06/2023	No	No

Editorial Notes

31/01/2025: The following changes were made to the trial record:
1. The scientific contact was changed.
2. The study hypothesis was changed.
3. The primary outcome measure was changed.
4. The secondary outcome measures were changed.
5. The inclusion criteria were changed.
6. The sponsor email was changed.
7. The publication and dissemination plan and intention to publish date were removed.
09/01/2025: The sponsor representative contact was updated in the plain English summary and study contacts.
17/12/2024: The sponsor email was changed.
19/11/2024: The following changes were made to the trial record:
1. The scientific contact was changed.
2. The overall end date was changed from 30/12/2024 to 03/10/2024.
3. The sponsor contact details were changed.
4. The intention to publish date was changed from 30/12/2025 to 03/10/2025.
5. The plain English summary was updated to reflect these changes.
05/09/2024: Contact details updated.
03/09/2024: Total final enrolment added.
02/09/2024: Sponsor details updated.
11/07/2024: The recruitment end date was changed from 31/08/2024 to 11/06/2024.
20/05/2024: The following changes were made to the trial record:
1. The inclusion criteria were changed.
2. The exclusion criteria were changed.
3. The recruitment end date was changed from 31/10/2024 to 31/08/2024.
4. The study participating centres Units 3 - 9 were added.
01/02/2024: The recruitment end date was changed from 18/01/2024 to 31/10/2024.
19/01/2024: The recruitment end date was changed from 31/01/2024 to 18/01/2024.
03/07/2023: The sponsor contact details were updated.
30/06/2023: The scientific contact was changed.
25/10/2022: The following changes were made to the trial record:
1. The ethics approval was added.
2. The interventions were changed.
3. The inclusion criteria were changed.
4. The exclusion criteria were changed.
5. The trial participating centre Re-Cognition Health was added.
6. A contact was added.
7. The intention to publish date was changed from 30/04/2025 to 30/12/2025.
8. The plain English summary was updated to reflect these changes.
07/06/2022: Internal review.
14/02/2022: Trial's existence confirmed by NHS HRA.