A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of RO7234292 (ISIS 443139) in Huntington's Disease Patients Who Participated in Prior Investigational Studies of RO7234292 (ISIS 443139)

• ClinicalTrials.gov Identifier: NCT03342053
• Recruitment Status: Completed
• First Posted: November 14, 2017
• Results First Posted: January 19, 2021
• Last Update Posted: March 24, 2022
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Huntington's Disease
• Intervention: Drug: RO7234292 (RG6042)
• Enrollment: 46

Participant Flow

Recruitment Details	Participant eligibility for the study was determined within 4 weeks prior to participant entry into the Treatment Period.
Pre-assignment Details

Arm/Group Title	RO7234292 Monthly	RO7234292 Bimonthly
Arm/Group Description	RO7234292 was administered intrathecally every 28 days for 14 months.	RO7234292 was administered intrathecally every 56 days for 14 months following 2 monthly doses to serve as a loading dose.
Period Title: Overall Study
Started	23	23
Completed	21	22
Not Completed	2	1
Reason Not Completed
Adverse Event	2	0
Withdrawal by Subject	0	1

Baseline Characteristics

Arm/Group Title		RO7234292 Monthly	RO7234292 Bimonthly	Total
Arm/Group Description		RO7234292 was administered intrathecally every 28 days for 14 months.	RO7234292 was administered intrathecally every 56 days for 14 months following 2 monthly doses to serve as a loading dose.	Total of all reporting groups
Overall Number of Baseline Participants		23	23	46
Baseline Analysis Population Description		[Not Specified]
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	23 participants	23 participants	46 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	23 100.0%	20 87.0%	43 93.5%
	>=65 years	0 0.0%	3 13.0%	3 6.5%
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	23 participants	23 participants	46 participants
		47.7 (9.3)	49.5 (11.3)	48.6 (10.3)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	23 participants	23 participants	46 participants
	Female	8 34.8%	10 43.5%	18 39.1%
	Male	15 65.2%	13 56.5%	28 60.9%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	23 participants	23 participants	46 participants
	Hispanic or Latino	0 0.0%	0 0.0%	0 0.0%
	Not Hispanic or Latino	23 100.0%	23 100.0%	46 100.0%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Race/Ethnicity, Customized [1]; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	23 participants	23 participants	46 participants
American Indian or Alaska Native		0 0.0%	0 0.0%	0 0.0%
Asian		0 0.0%	0 0.0%	0 0.0%
Native Hawaiian or Other Pacific Islander		0 0.0%	0 0.0%	0 0.0%
Black or African American		0 0.0%	0 0.0%	0 0.0%
White		22 95.7%	23 100.0%	45 97.8%
More than one race		0 0.0%	0 0.0%	0 0.0%
Other		1 4.3%	0 0.0%	1 2.2%
		[1] Measure Analysis Population Description: One participant's race is known, was reported but cannot be classified in Roche database

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Adverse Events
Description	Adverse Events include Adverse Events that started at or after Date/Time of First Exposure to Treatment and procedure-related Adverse Events occurring before the start of treatment.
Time Frame	From baseline up to 18 months

Outcome Measure Data

Analysis Population Description

Safety population comprising all participants that were randomized and received at least one dose of RO7234292.

Arm/Group Title	RO7234292 Monthly	RO7234292 Bimonthly
Arm/Group Description:	RO7234292 was administered intrathecally every 28 days for 14 months.	RO7234292 was administered intrathecally every 56 days for 14 months following 2 monthly doses to serve as a loading dose.
Overall Number of Participants Analyzed	23	23
Measure Type: Number; Unit of Measure: Percentage of participants
	100	95.7

2. Secondary Outcome

Title	RO7234292 CSF Trough Concentrations by Study Day Prior to Monthly and Bimonthly IT Administration of 120 mg RO7234292 (Primary Analysis)
Description	[Not Specified]
Time Frame	From baseline to Day 421

Outcome Measure Data

Analysis Population Description

CSF Trough Concentrations were reported following study drug administration. Data for Bi-monthly arm was not collected on days 57, 113, 169, 225, 281, 337, 393. Here "Number Analyzed" represents number of participants from whom samples were collected and analyzed.

Arm/Group Title		RO7234292 Monthly	RO7234292 Bimonthly
Arm/Group Description:		RO7234292 was administered intrathecally every 28 days for 14 months.	RO7234292 was administered intrathecally every 56 days for 14 months following 2 monthly doses to serve as a loading dose.
Overall Number of Participants Analyzed		23	23
Geometric Mean (Full Range); Unit of Measure: ng/mL
Day 29	Number Analyzed	22 participants	21 participants
		2.59; (1.31 to 12.7)	2.52; (0.817 to 7.85)
Day 57	Number Analyzed	22 participants	0 participants
		3.47; (1.43 to 19.2)
Day 85	Number Analyzed	22 participants	21 participants
		3.70; (1.38 to 7.34)	1.39; (0.164 to 5.74)
Day 113	Number Analyzed	22 participants	0 participants
		3.97; (1.96 to 16.4)
Day 141	Number Analyzed	21 participants	21 participants
		4.57; (1.72 to 13)	1.35; (0.396 to 3.69)
Day 169	Number Analyzed	22 participants	0 participants
		4.47; (2.04 to 12.7)
Day 197	Number Analyzed	21 participants	21 participants
		4.58; (1.74 to 8.61)	1.26; (0.281 to 3.37)
Day 225	Number Analyzed	21 participants	0 participants
		5.21; (1.63 to 14.3)
Day 253	Number Analyzed	20 participants	20 participants
		4.96; (1.56 to 11.8)	1.45; (0.417 to 3.76)
Day 281	Number Analyzed	18 participants	0 participants
		4.96; (1.30 to 12.4)
Day 309	Number Analyzed	18 participants	21 participants
		5.53; (1.74 to 11.6)	1.35; (0.195 to 2.77)
Day 337	Number Analyzed	15 participants	0 participants
		5.12; (2.17 to 10.5)
Day 365	Number Analyzed	18 participants	21 participants
		4.50; (1.18 to 13.9)	1.45; (0.507 to 2.95)
Day 393	Number Analyzed	17 participants	0 participants
		3.10; (0.220 to 9.83)
Day 421	Number Analyzed	18 participants	21 participants
		3.01; (0.239 to 9.54)	1.34; (0.325 to 2.45)

3. Secondary Outcome

Title	CSF mHTT Protein Concentration Logarithmic Value Change in Geometric Mean (95%CI) From Baseline
Description	The results of the planned analysis related to mHTT protein levels in CSF are reported
Time Frame	From Baseline to Day 421

Outcome Measure Data

Analysis Population Description

ITT Population. The data for Bi-monthly arm was not collected on days 113, 169, 225, 281, 337, 393. Here "Number Analyzed" represents number of participants from whom samples were collected and analyzed

Arm/Group Title		RO7234292 Monthly	RO7234292 Bimonthly
Arm/Group Description:		RO7234292 was administered intrathecally every 28 days for 14 months.	RO7234292 was administered intrathecally every 56 days for 14 months following 2 monthly doses to serve as a loading dose.
Overall Number of Participants Analyzed		23	23
Geometric Mean (95% Confidence Interval); Unit of Measure: Log (10) fmol/L
Day 29	Number Analyzed	19 participants	23 participants
		-27.95; (-38.37 to -15.76)	-21.84; (-33.22 to -8.52)
Day 57	Number Analyzed	23 participants	2 participants
		-26.90; (-40.95 to -9.50)	10.11; (-41.68 to 107.88)
Day 85	Number Analyzed	22 participants	23 participants
		-50.30; (-59.00 to -39.75)	-32.63; (-44.31 to -18.50)
Day 113	Number Analyzed	22 participants	0 participants
		-49.11; (-58.77 to -37.18)
Day 141	Number Analyzed	22 participants	23 participants
		-54.02; (-61.05 to -45.72)	-41.76; (-50.59 to -31.35)
Day 169	Number Analyzed	22 participants	0 participants
		-42.33; (-53.66 to -28.23)
Day 197	Number Analyzed	22 participants	23 participants
		-40.79; (-52.59 to -26.05)	-36.48; (-48.99 to -20.89)
Day 225	Number Analyzed	22 participants	0 participants
		-47.01; (-58.69 to -32.02)
Day 253	Number Analyzed	21 participants	22 participants
		-43.63; (-55.39 to -28.77)	-41.06; (-53.19 to -25.78)
Day 281	Number Analyzed	19 participants	0 participants
		-40.29; (-58.63 to -13.80)
Day 309	Number Analyzed	18 participants	23 participants
		-36.67; (-50.11 to -19.60)	-40.82; (-52.37 to -26.46)
Day 337	Number Analyzed	16 participants	0 participants
		-42.71; (-58.93 to -20.07)
Day 365	Number Analyzed	19 participants	23 participants
		-49.55; (-62.02 to -32.98)	-55.07; (-65.46 to -41.57)
Day 393	Number Analyzed	18 participants	0 participants
		-41.55; (-59.46 to -15.74)
Day 421	Number Analyzed	19 participants	23 participants
		-45.45; (-56.21 to -32.03)	-41.51; (-52.22 to -28.39)

4. Secondary Outcome

Title	Mean Percentage Change in Ventricular Volume Boundary Shift Integral From Baseline to 15 Months
Description	[Not Specified]
Time Frame	Baseline up to 15 months

Outcome Measure Data

Analysis Population Description

Here "Number of Participants Analyzed" represents number of participants from whom data were collected and analyzed. Only data that passed the QC imaging process were included in the analysis.

Arm/Group Title	RO7234292 Monthly	RO7234292 Bimonthly
Arm/Group Description:	RO7234292 was administered intrathecally every 28 days for 14 months.	RO7234292 was administered intrathecally every 56 days for 14 months following 2 monthly doses to serve as a loading dose.
Overall Number of Participants Analyzed	20	18
Mean (Standard Deviation); Unit of Measure: Percentage change
	46.09 (32.14)	18.77 (10.36)

5. Secondary Outcome

Title	Mean Percentage Change in Caudate Volume Boundary Shift Integral From Baseline to 15 Months
Description	[Not Specified]
Time Frame	Baseline up to 15 months

Outcome Measure Data

Analysis Population Description

Here "Number of Participants Analyzed" represents number of participants from whom data were collected and analyzed.

Arm/Group Title	RO7234292 Monthly	RO7234292 Bimonthly
Arm/Group Description:	RO7234292 was administered intrathecally every 28 days for 14 months.	RO7234292 was administered intrathecally every 56 days for 14 months following 2 monthly doses to serve as a loading dose.
Overall Number of Participants Analyzed	22	18
Mean (Standard Deviation); Unit of Measure: Percentage change
	8.64 (6.26)	5.67 (2.22)

6. Secondary Outcome

Title	Mean Percentage Change in Whole Brain Volume Boundary Shift Integral From Baseline to 15 Months
Description	[Not Specified]
Time Frame	Baseline up to 15 months

Outcome Measure Data

Analysis Population Description

Here "Number of Participants Analyzed" represents number of participants from whom data were collected and analyzed.

Arm/Group Title	RO7234292 Monthly	RO7234292 Bimonthly
Arm/Group Description:	RO7234292 was administered intrathecally every 28 days for 14 months.	RO7234292 was administered intrathecally every 56 days for 14 months following 2 monthly doses to serve as a loading dose.
Overall Number of Participants Analyzed	13	18
Mean (Standard Deviation); Unit of Measure: Percentage change
	1.63 (1.41)	0.89 (0.92)

7. Secondary Outcome

Title	EEG Parameters: Mean Change From Baseline to 15 Months in Absolute Power [8-12Hz]
Description	[Not Specified]
Time Frame	Baseline to 15 Months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	RO7234292 Monthly	RO7234292 Bimonthly
Arm/Group Description:	RO7234292 was administered intrathecally every 28 days for 14 months.	RO7234292 was administered intrathecally every 56 days for 14 months following 2 monthly doses to serve as a loading dose.
Overall Number of Participants Analyzed	17	19
Mean (Standard Deviation); Unit of Measure: log10(mircrovolts^2)
	0.11 (0.18)	0.02 (0.21)

8. Secondary Outcome

Title	Mean Change From Baseline in Huntington's Disease Cognitive Assessment Battery Composite Score
Description	HD Cognitive Assessment Battery (HD-CAB) was developed to assess cognitive dysfunction in late premanifest and early manifest HD patients. HD-CAB combines scores from six cognitive tests: SDMT, Self-Paced Tapping, Emotional Recognition, CANTAB One Touch Stocking, Hopkins Verbal Learning Test - Revised, and Trail-Making Test. A multi-component score is derived by transforming the subject's score on each cognitive test to a z-score. Using z-scores permits the combination of test scores with different scales. Unlike other measures that use an external reference population to create z-scores, HD-CAB uses the baseline data of the study. Individually, for each of the six cognitive tests, the study baseline mean is subtracted from the subject's score, and this value is divided by the study baseline standard deviation. The six z-scores are averaged to produce the HD-CAB score. A positive change from baseline indicates improvement in cognitive function; a negative change indicates worsening.
Time Frame	Baseline to 15 Months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	RO7234292 Monthly	RO7234292 Bimonthly
Arm/Group Description:	RO7234292 was administered intrathecally every 28 days for 14 months.	RO7234292 was administered intrathecally every 56 days for 14 months following 2 monthly doses to serve as a loading dose.
Overall Number of Participants Analyzed	17	21
Mean (Standard Deviation); Unit of Measure: z-score
	-0.33 (0.27)	-0.15 (0.23)

Adverse Events

Time Frame	From baseline to up to 18 months
Adverse Event Reporting Description	Safety population comprising all participants that were randomized and received at least one dose of RO7234292
Arm/Group Title	RO7234292 Monthly		RO7234292 Bimonthly
Arm/Group Description	RO7234292 was administered intrathecally every 28 days for 14 months.		RO7234292 was administered intrathecally every 56 days for 14 months following 2 monthly doses to serve as a loading dose.
All-Cause Mortality
	RO7234292 Monthly		RO7234292 Bimonthly
	Affected / at Risk (%)		Affected / at Risk (%)
Total	1/23 (4.35%)		0/23 (0.00%)
Serious Adverse Events
	RO7234292 Monthly		RO7234292 Bimonthly
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/23 (17.39%)		3/23 (13.04%)
Infections and infestations
Myelitis † 1	1/23 (4.35%)	1	0/23 (0.00%)	0
Injury, poisoning and procedural complications
Fall † 1	0/23 (0.00%)	0	1/23 (4.35%)	1
Skin laceration † 1	0/23 (0.00%)	0	1/23 (4.35%)	1
Cervical vertebral fracture † 1	0/23 (0.00%)	0	1/23 (4.35%)	1
Chest injury † 1	1/23 (4.35%)	1	0/23 (0.00%)	0
Concussion † 1	0/23 (0.00%)	0	1/23 (4.35%)	1
Meningitis chemical † 1	1/23 (4.35%)	1	0/23 (0.00%)	0
Rib fracture † 1	1/23 (4.35%)	1	0/23 (0.00%)	0
Spinal column injury † 1	0/23 (0.00%)	0	1/23 (4.35%)	1
Thoracic vertebral fracture † 1	1/23 (4.35%)	1	0/23 (0.00%)	0
Nervous system disorders
Cerebrovascular accident † 1	1/23 (4.35%)	1	0/23 (0.00%)	0
Hemiparesis † 1	1/23 (4.35%)	1	0/23 (0.00%)	0
Hydrocephalus † 1	1/23 (4.35%)	1	0/23 (0.00%)	0
Hyporeflexia † 1	1/23 (4.35%)	1	0/23 (0.00%)	0
Neuritis † 1	1/23 (4.35%)	1	0/23 (0.00%)	0
Radiculopathy † 1	1/23 (4.35%)	1	0/23 (0.00%)	0
Psychiatric disorders
Completed suicide † 1	1/23 (4.35%)	1	0/23 (0.00%)	0
Suicide attempt † 1	1/23 (4.35%)	1	1/23 (4.35%)	1
Respiratory, thoracic and mediastinal disorders
Pneumothorax † 1	1/23 (4.35%)	1	0/23 (0.00%)	0
1 Term from vocabulary, MedDRA 22.1; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	RO7234292 Monthly		RO7234292 Bimonthly
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	22/23 (95.65%)		22/23 (95.65%)
Ear and labyrinth disorders
Vertigo † 1	2/23 (8.70%)	2	0/23 (0.00%)	0
Gastrointestinal disorders
Diarrhoea † 1	0/23 (0.00%)	0	5/23 (21.74%)	6
Nausea † 1	3/23 (13.04%)	3	3/23 (13.04%)	5
Vomiting † 1	2/23 (8.70%)	2	2/23 (8.70%)	2
General disorders
Fatigue † 1	3/23 (13.04%)	3	1/23 (4.35%)	1
Gait disturbance † 1	6/23 (26.09%)	14	0/23 (0.00%)	0
Injection site pain † 1	2/23 (8.70%)	3	4/23 (17.39%)	4
Puncture site pain † 1	2/23 (8.70%)	3	2/23 (8.70%)	4
Infections and infestations
Ear infection † 1	3/23 (13.04%)	3	0/23 (0.00%)	0
Gastroenteritis † 1	2/23 (8.70%)	2	1/23 (4.35%)	1
Nasopharyngitis † 1	9/23 (39.13%)	14	10/23 (43.48%)	15
Upper respiratory tract infection † 1	3/23 (13.04%)	4	1/23 (4.35%)	2
Urinary tract infection † 1	2/23 (8.70%)	2	2/23 (8.70%)	4
Injury, poisoning and procedural complications
Contusion † 1	6/23 (26.09%)	21	5/23 (21.74%)	5
Fall † 1	18/23 (78.26%)	87	12/23 (52.17%)	17
Head injury † 1	2/23 (8.70%)	2	0/23 (0.00%)	0
Ligament sprain † 1	1/23 (4.35%)	1	2/23 (8.70%)	2
Limb injury † 1	3/23 (13.04%)	3	0/23 (0.00%)	0
Post lumbar puncture syndrome † 1	4/23 (17.39%)	10	5/23 (21.74%)	6
Procedural headache † 1	0/23 (0.00%)	0	2/23 (8.70%)	4
Procedural pain † 1	7/23 (30.43%)	19	12/23 (52.17%)	15
Skin abrasion † 1	7/23 (30.43%)	11	4/23 (17.39%)	6
Skin laceration † 1	2/23 (8.70%)	2	3/23 (13.04%)	3
Investigations
CSF protein increased † 1	2/23 (8.70%)	3	1/23 (4.35%)	1
CSF white blood cell count increased † 1	2/23 (8.70%)	2	0/23 (0.00%)	0
Musculoskeletal and connective tissue disorders
Arthralgia † 1	3/23 (13.04%)	4	2/23 (8.70%)	2
Back pain † 1	2/23 (8.70%)	2	4/23 (17.39%)	6
Pain in extremity † 1	3/23 (13.04%)	6	2/23 (8.70%)	2
Nervous system disorders
Balance disorder † 1	3/23 (13.04%)	3	1/23 (4.35%)	1
Cerebral ventricle dilatation † 1	2/23 (8.70%)	2	0/23 (0.00%)	0
Dizziness † 1	2/23 (8.70%)	2	2/23 (8.70%)	2
Dysarthria † 1	2/23 (8.70%)	3	0/23 (0.00%)	0
Dyskinesia † 1	2/23 (8.70%)	2	0/23 (0.00%)	0
Headache † 1	6/23 (26.09%)	13	4/23 (17.39%)	10
Hyperkinesia † 1	2/23 (8.70%)	2	0/23 (0.00%)	0
Lumbar radiculopathy † 1	2/23 (8.70%)	2	0/23 (0.00%)	0
Motor dysfunction † 1	3/23 (13.04%)	3	0/23 (0.00%)	0
Paraesthesia † 1	2/23 (8.70%)	2	0/23 (0.00%)	0
Parkinsonism † 1	2/23 (8.70%)	2	0/23 (0.00%)	0
Presyncope † 1	2/23 (8.70%)	2	0/23 (0.00%)	0
Syncope † 1	0/23 (0.00%)	0	2/23 (8.70%)	2
Psychiatric disorders
Anxiety † 1	2/23 (8.70%)	2	0/23 (0.00%)	0
Depressed mood † 1	2/23 (8.70%)	2	2/23 (8.70%)	2
Depression † 1	4/23 (17.39%)	4	2/23 (8.70%)	2
Insomnia † 1	1/23 (4.35%)	1	2/23 (8.70%)	2
Irritability † 1	2/23 (8.70%)	3	0/23 (0.00%)	0
Tension † 1	2/23 (8.70%)	2	0/23 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Cough † 1	0/23 (0.00%)	0	2/23 (8.70%)	2
Rhinorrhoea † 1	1/23 (4.35%)	1	2/23 (8.70%)	3
Skin and subcutaneous tissue disorders
Hyperhidrosis † 1	2/23 (8.70%)	3	0/23 (0.00%)	0
Vascular disorders
Haematoma † 1	4/23 (17.39%)	7	2/23 (8.70%)	2
1 Term from vocabulary, MedDRA 22.1; † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.

Results Point of Contact

• Name/Title: Medical Communications
• Organization: Hoffmann-La Roche
• Phone: 800 821-8590
• EMail: genentech@druginfo.com

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT03342053
• Other Study ID Numbers: BN40697
• First Submitted: October 31, 2017
• First Posted: November 14, 2017
• Results First Submitted: October 7, 2020
• Results First Posted: January 19, 2021
• Last Update Posted: March 24, 2022