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A Randomized, Multicenter, Double-Blind, Placebo-Controlled, Phase III Clinical Study to Evaluate the Efficacy and Safety of Intrathecally Administered RO7234292 (RG6042) in Patients With Manifest Huntington's Disease

A Study to Evaluate the Efficacy and Safety of Intrathecally Administered RO7234292 (RG6042) in Patients With Manifest Huntington's Disease

791

The demographic characteristics were balanced between the active treatment groups and the placebo group. The mean (SD) age of patients was 47.8 years (9.6) in Q8W group, 47.5 years (9.3) in Q16W group, and 48.7 years (9.9) in placebo group. The proportion of patients by gender was male 57.31%, female 42.69% in Q8W group, male 50.96%, female 49.04% in Q16W group, and male 56.54%, female 43.46% in placebo group. As for the race, the majority of patients were of white race in all three treatment groups (94.62% in Q8W group, 93.87% in Q16W group, and 94.62% in placebo group). Asian patients were 1.92% in Q8W group, 1.53% in Q16W group, and 1.15% in placebo group.

A total of 791 patients were enrolled in the study; 263 in Q8W group,264 in Q16W group, and 264 in placebo group. Of these 791 patients, 260 patients received tominersen 120 mg Q8W, 261 patients received 120 mg Q16W, and 260 patients received placebo.

A similar proportion of patients experienced at least one adverse event were 92.3% in Q8W group, 90.0% in Q16W group, and 93.1% in placebo group. Deaths were reported one in Q8W group, 2 in Q16W group, and 3 in placebo group. None of them were considered related to tominersen. The incidence of SAEs was 50 out of 263 patients (19.01%) in Q8W group, 28 out of 264 patients (10.61%) in Q16W group, and 34 out of 264 patients (12.88%) in placebo group.

Sponsor decided to discontinue study treatment in this study based on independent review committee (iDMC). Therefore the efficacy assessment at Week 69 was performed rather than the planned assessment at Week 101. and the primary endpoint for the study was not met. In the ITT population (260 patients in Q8W group, 261 patients in Q16 group, and 260 patients in placebo group), at Week 69 the LS mean (SE) change in Composite Unified Huntington's Disease Rating Scale (cUHDRS) score from baseline was -1.173 (0.091) in Q8W group and -0.793 (0.093) in Q16W group compared to -0.630 (0.091) in placebo group.

At Week 69, the LS mean (SE) change in the Total Functional Capacity (TFC) score from baseline was -1.284 (0.124) in Q8W group, and -0.921 At Week 69, the LS mean (SE) change in the Total Functional Capacity (TFC) score from baseline was -1.284 (0.124) in Q8W group, and -0.921 (0.126) in Q16W group compared to -0.883 (0.124) in placebo group. At Week 69, the LS mean (SE) change in Total Motor Score (TMS) from baseline was 4.028 (0.575) in Q8W group and 3.524 (0.583) in Q16W group compared to 3.513 (0.573) in placebo group. At Week 69, the LS mean (SE) Symbol Digit Modalities Test (SDMT) score from baseline was -2.641 (0.380) in Q8W group and -0.996 (0.385) in Q16W group compared to -0.216 (0.379) in placebo group. At Week 69, the LS mean (SE) Stroop Word Reading (SWR) Test score was 5.224 (0.803) in Q8W group and -3.949 (0.815) in Q16W group compared to -2.555 (0.802) in placebo group. At Week 69, the LS mean (SE) Clinical Global Impression, Severity Scale (CGI-S) score was 0.662 (0.093) in Q8W group and 0.640 (0.094) in Q16W group compared to 0.545 (0.093) in placebo group. At Week 69, a similar proportion of patients had decrease in Total Functional Capacity (TFC) score by at least 1 point from baseline in the active treatment groups (Q8W and Q16W) and the placebo group. At Week 69, the proportion of patients who had at least 1.2 points decrease in Composite Unified Huntington's Disease Rating Scale (cUHDRS) score from baseline was higher in Q8W group compared to placebo; whereas, it was similar in Q16W group compared to placebo group. At Week 69, a similar proportion of patients were rated as unchanged or improved on the Clinical Global Impression, Change Scale (CGI-C) in the active treatment groups (Q8W and Q16W) compared to the placebo group.

The study treatment was terminated early at the discretion of the sponsor based on an independent review committee (iDMC) recommendation, and the primary efficacy endpoint of the study was not met. The results of secondary efficacy endpoints were in general consistent with the primary analysis.

Yes

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Chugai Pharmaceutical Co., Ltd.

1-1 NIHONBASHI-MUROMACHI 2-CHOME, CHUO-KU, Tokyo

clinical-trials@chugai-pharm.co.jp

Chugai Pharmaceutical Co., Ltd.

1-1 NIHONBASHI-MUROMACHI 2-CHOME, CHUO-KU, Tokyo

+81-120189706

clinical-trials@chugai-pharm.co.jp

completed

Sept. 30, 2019

Interventional

A randomised, Double Blind, Placebo-Controlled, Phase III Clinical Trial

treatment purpose

3

- Manifest HD diagnosis, defined as a DCL score of 4
- Independence Scale (IS) score >= 70
- Genetically confirmed disease by direct DNA testing with a CAP score >400
- Clinical assessment to ensure individual has intact functional independence at baseline to maintain self-care and core activities of daily living (ADLs).

- Any serious medical condition or clinically significant laboratory, or vital sign abnormality at screening that, in the investigator's judgment, precludes the patient's safe participation in and completion of the study
- Pregnant or breastfeeding, or intending to become pregnant during the study or within 5 months after the final dose of study drug

Both

Huntington's Disease

investigational material(s)
Generic name etc : Tominersen (RO7234292)
INN of investigational material : tominersen
Therapeutic category code : 119 Other agents affecting central nervous system
Dosage and Administration for Investigational material : Intrathecally administered every 8 weeks
Generic name etc : Tominersen (RO7234292)
INN of investigational material : tominersen
Therapeutic category code : 119 Other agents affecting central nervous system
Dosage and Administration for Investigational material : Intrathecally administered every 16 weeks, also receive placebo at alternate weeks to keep the blind

control material(s)
Generic name etc : Placebo
INN of investigational material : -
Therapeutic category code : --- Other
Dosage and Administration for Investigational material : Intrathecally administered every 8 weeks

efficacy
- Change from Baseline in the Composite Unified Huntington's Disease Rating Scale (cUHDRS) [ Time Frame: Baselined, Week 101 ].
- Change From Baseline in the TFC Score [ Time Frame: Baseline, Week 101 ]

efficacy
- Change From Baseline in Total Motor Score (TMS) [ Time Frame: Baseline, Week 101 ]
- Change From Baseline in Symbol Digit Modalities Test (SDMT) [ Time Frame: Baseline, Week 101 ]
- Change From Baseline in Stroop Word Reading (SWR) Test [ Time Frame: Baseline, Week 101 ]
- Change From Baseline in the Clinical Global Impression, Severity Scale (CGI-S) [ Time Frame: Baseline, Week 101 ]
- Percentage of Patients with a Decrease From Baseline of >=1 point on the TFC [ Time Frame: Baseline, Week101 ]
- Percentage of Patients With a Decline From Baseline of >=1.2 Points on the cUHDRS [ Time Frame: Baseline, Week 101 ]
- Percentage of Patients With an Unchanged or Improved Score on the Clinical Global Impression, Change Scale (CGI-C) Score [ Time Frame: Baseline to Week 101 ]
safety
- Percentage of Participants with Adverse Events [ Time Frame: Up to 117 Weeks (29 months) ]
- Change From Baseline in Montreal Cognitive Assessment (MoCA) [ Time Frame: Screening, Baseline, Weeks 5, 21, 37, 53, 69, 85 and 101 and early treatment termination ]
- Percentage of Participants With Suicidal Ideation or Behavior, as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score [ Time Frame: Screening, Baseline, Weeks 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89, 93, 97, 101, end of treatment for early treatment termination and at early treatment termination ]
pharmacokinetics
- Concentration of RO7234292 in Plasma [ Time Frame: Baseline, Weeks 13, 21, 37, 53, 69, 85, and 101 and early treatment termination ]
- Trough Concentration of RO7234292 in CSF [ Time Frame: Baseline, Weeks 13, 21, 37, 53, 69, 85, and 101 and early treatment termination ]
other
- Incidence of Anti-Drug Antibodies (ADAs) [ Time Frame: Baseline, Weeks 13, 21, 37, 53, 69, 85, and 101 and early treatment termination and safety follow-up visit ]
- Titer and Antibody Subtype, determined if ADAs are Identified [ Time Frame: Baseline, Weeks 13, 21, 37, 53, 69, 85, and 101 and early treatment termination and safety follow-up visit ]
- Change From Baseline in CSF mHTT Protein Level [ Time Frame: Baseline, Week 101 ]
- Change From Baseline in Whole and Regional Brain Volumes, as detrmined by structural magnetic resonance imaging (MRI) [ Time Frame: Baseline, Week 101 ]
17.Change From Baseline in CSF Neurofilament Light Chain (NfL) Proteint Level [ Time Frame: Baseline, Week 101

June. 26, 2019