A Study of RO7123520 to Evaluate the Safety and Efficacy in Participants With Moderately To Severely Active Rheumatoid Arthritis (RA) Who Are Inadequately Responding to Anti-Tumor Necrosis Factor (TNF)-Alpha Therapy

A Randomized, Double-Blind, Placebo-Controlled, Multi-Center Phase II Study to Evaluate The Safety and Efficacy of RO7123520 as Adjunct Treatment in Patients With Moderately to Severely Active Rheumatoid Arthritis and an Inadequate Response to TNF-alpha Inhibitors

Status

Terminated

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03001219

Enrollment

109

Registered

2016-12-22

Start date

2016-12-22

Completion date

2018-11-06

Last updated

2020-01-29

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Rheumatoid Arthritis

Brief summary

This is a Phase IIa/b double-blind, placebo-controlled, randomized, parallel group, multicenter study to evaluate the safety and efficacy of RO7123520 as adjunctive therapy in participants with RA who are inadequately responding to standard-of-care (methotrexate and anti-TNF-alpha therapy). Part 1 of the study will evaluate safety. Part 2 will evaluate efficacy and safety. Part 3 will evaluate dose-ranging efficacy. Participants will have the option of continuing to the extension period of the study.

Interventions

DRUGAnti-TNF-alpha

Participants will continue their pre-trial anti-TNF-alpha therapy at a stable dose.

DRUGMethotrexate

Participants will continue their pre-trial methotrexate therapy at a stable dose.

DRUGPlacebo

Participants will receive intravenous infusion of placebo.

DRUGRO7123520

Participants will receive intravenous infusion of RO7123520.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* Diagnosis of adult-onset RA as defined by the ACR 2010 criteria, for at least 6 months before screening * Moderately to severely active RA as defined by at least 4/28 tender joints and at least 4/28 swollen joints, and a DAS28 greater than or equal to (≥) 3.2 * For Part 2 only: Active synovitis and/or osteitis as determined by contrast-enhanced magnetic resonance imaging * Participants must be taking stable dose of anti-TNF-alpha therapies * Participants on stable oral glucocorticoids within 6 weeks of planned randomization * Participants taking non-steroidal anti-inflammatory drugs (NSAIDs) intermittently (up to 2-3 times weekly) for short-term relief of pain and participants on regular NSAID use (on stable dose for ≥ 4 weeks)

Exclusion criteria

* Parenteral glucocorticoids administration (intramuscular, IV) of ≥50 mg within 6 weeks or less than or equal to (≤) 50 milligrams (mg) within 4 weeks prior to planned randomization, or scheduled parenteral administrations during the study * Joint(s) injected with intra-articular glucocorticoids or hyaluronic acid within 6 weeks prior to planned randomization * Active inflammatory diseases of the joints not related to RA * Systemic autoimmune disease other than RA * Juvenile idiopathic arthritis or juvenile RA and/or RA developed before the age of 16 * Active fibromyalgia that makes appropriate assessment of RA disease activity challenging in the opinion of the Investigator * RA participants functional status class IV according to the ACR 1991 criteria * Participants with severe chronic or recurrent viral, bacterial, parasitic, or fungal infections * History of active hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV) infection * Any identified confirmed congenital or acquired immunodeficiency * Abnormal laboratory values and liver function test * Myocardial infarction within less than 6 months prior to participation in the study * Severe central or peripheral nervous system diseases

Design outcomes

Primary

Measure	Time frame	Description
Change From Baseline in Bone Mineral Density Lumbar Spine L1-L4 as Assessed by Dual Energy X-ray Absorptiometry (DEXA) Scans	Baseline, Week 12 of PoC and Week 12 of Extension Period Analysis (overall study week 24)	—
Percentage of Participants With Adverse Events	Baseline to last participant last visit (approximately 2 years)	An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.
Proportion of Participants Achieving an American College of Rheumatology (ACR) 50 Response at Week 12	Week 12 of PoC and Week 12 of Extension Period Analysis (overall study week 24)	The ACR50 is a composite measure defined as both improvement of 50% in the number of tender and number of swollen joints, and a 50% improvement in three of the following five criteria: patient global assessment, physician global assessment, functional ability measure \[most often Health Assessment Questionnaire (HAQ)\], visual analog pain scale, and erythrocyte sedimentation rate or C-reactive protein (CRP). The ACR is reported as percent improvement at discrete time points.
Percentage of Participants With Anti-Drug Antibodies	Baseline	—

Secondary

Measure	Time frame	Description
Percentage of Participants Achieving ACR20 Response at Week 12	Week 12 of PoC and Week 12 of Extension Period Analysis (overall study week 24)	The ACR20 is a composite measure defined as both improvement of 20% in the number of tender and number of swollen joints, and a 20% improvement in three of the following five criteria: patient global assessment, physician global assessment, functional ability measure \[most often Health Assessment Questionnaire (HAQ)\], visual analog pain scale, and erythrocyte sedimentation rate or C-reactive protein (CRP). The ACR is reported as percent improvement at discrete time points.
Percentage of Participants Achieving ACR70 Response at Week 12	Week 12 of PoC and Week 12 of Extension Period Analysis (overall study week 24)	The ACR70 is a composite measure defined as both improvement of 70% in the number of tender and number of swollen joints, and a 70% improvement in three of the following five criteria: patient global assessment, physician global assessment, functional ability measure \[most often Health Assessment Questionnaire (HAQ)\], visual analog pain scale, and erythrocyte sedimentation rate or C-reactive protein (CRP). The ACR is reported as percent improvement at discrete time points.
Change From Baseline in Simple Disease Activity Index (SDAI) Score at Week 12	Baseline, Week 12 of PoC and Week 12 of Extension Period Analysis (overall study week 24)	The SDAI consists of 5 parameters used to assess RA disease activity: 28-joint count assessments of tenderness and swelling, participant and investigator global assessments, and CRP levels. A composite score is produced, with remission defined as an SDAI of \<3.3, low disease activity as ≤11, moderate disease activity as ≤26 and high disease activity as \>26.
Change From Baseline in Clinical Disease Activity Index (CDAI) Score at Week 12	Baseline, Week 12 of PoC and Week 12 of Extension Period Analysis (overall study week 24)	The CDAI for Rheumatoid Arthritis (RA) assesses the severity of the disease using clinical data. It consists of the Patient Global disease Activity (PGA) estimate and the Evaluator Global disease Activity (EGA) estimate, each of which represent assessments of disease activity on a scale of 1-10, with 10 being maximum activity.
Serum RO7123520 Concentration	Pre-dose (0 hour), 1 hour post infusion (duration of infusion: approximately 1 hour) on Days 1, 14, 28, 56; Pre-dose (0 hour) on Days 84, 112	—
Synovial Fluid RO7123520 Concentration	Pre-dose (0 hour) on Days 1, 84	—
Change From Baseline in the Stanford Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12	Baseline, Week 12 of PoC and Week 12 of Extension Period Analysis (overall study week 24)	The HAQ-DI is a 20-item, validated questionnaire used to assess difficulty in performing activities of daily living. The questionnaire assesses eight domains of physical functioning: Dressing and Grooming (2 items), Hygiene (3 items), Arising (2 items), Reach (2 items), Eating (3 items), Grip (3 items), Walking (2 items), Common Daily Activities (3 items). The questions assess usual abilities ranging from 0 without any difficulty to 3 unable to do. A lower HAQ-DI score indicates better quality of life. Subscale scores are combined and the mean value is reported for each arm per timepoint.
Change From Baseline in Disease Activity Score 28 (DAS28) at Week 12	Baseline, Week 12 of PoC and Week 12 of Extension Period Analysis (overall study week 24)	The DAS28 is a combined index for measuring disease activity in RA; the 28 refers to the number of joints included in the assessment. The index includes swollen and tender joint counts, acute phase response, and general arthritis disease activity status. An overall disease activity score of 5.1 or greater implies active disease, less than 3.2 implies low disease activity, and less that 2.6 implies disease remission.
Percentage of Participants Achieving DAS28 Remission at Week 12	Week 12 of PoC and Week 12 of Extension Period Analysis (overall study week 24)	The DAS28 is a combined index for measuring disease activity in RA; the 28 refers to the number of joints included in the assessment. The index includes swollen and tender joint counts, acute phase response, and general arthritis disease activity status. An overall disease activity score of 5.1 or greater implies active disease, less than 3.2 implies low disease activity, and less that 2.6 implies disease remission.
Percentage of Participants Achieving CDAI Remission at Week 12	Week 12 of PoC and Week 12 of Extension Period Analysis (overall study week 24)	The CDAI for Rheumatoid Arthritis (RA) assesses the severity of the disease using clinical data. It consists of the Patient Global disease Activity (PGA) estimate and the Evaluator Global disease Activity (EGA) estimate, each of which represent assessments of disease activity on a scale of 1-10, with 10 being maximum activity. CDAI remission is defined as a score of less than or equal to 2.8.

Countries

Argentina, Austria, Colombia, Germany, Guatemala, Italy, Mexico, Peru, Spain, United Kingdom, United States

Participant flow

Recruitment details

Adult men and women with moderate to severe active rheumatoid arthritis (RA) who experience an inadequate response to disease-modifying anti-rheumatic drug (DMARD) therapy with MTX plus anti-TNF-a therapy.

Pre-assignment details

Arms are not mutually exclusive. Proof of Concept: 109 total participants enrolled. Extension Period Analysis: 106 participants from the previous groups, including placebo, received 360 (n=9) or 810 mg/dose (n=97) of RO7123520. Part 3 was not conducted due to early study termination.

Participants by arm

Arm	Count
PoC Placebo to Extension Period Analysis RO7123520 In the Proof of Concept (PoC) period, participants received placebo (IV saline matched to RO7123520) + pre-trial anti-TNF-alpha and methotrexate (MTX), on Days 1, 14, 28, and 56. Participants from this group that continued to the Extension Period Analysis period were assigned RO7123520 + pre-trial anti-TNF-alpha and MTX at either 360 or 810 mg/dose up to Week 20 of the Extension Period (overall study Week 32).	37
RO70123520 360 or 810 mg/Dose In the PoC period, participants not assigned placebo received RO7123520 + pre-trial anti-TNF-alpha and MTX at 810 mg/dose on Days 1, 14, 28, and 56. Participants continuing to the Extension Period Analysis period received 360 or 810 mg/dose up to Week 20 of the Extension Period (overall study Week 32).	97
Total	134

Withdrawals & dropouts

Period	Reason	FG000	FG001
Extension Period Analysis	Adverse Event	1	1
Extension Period Analysis	Participant Non-Compliance	0	1
Extension Period Analysis	Physician Decision	0	1
Extension Period Analysis	Protocol Deviation	0	1
Extension Period Analysis	Study Termination by Sponsor	0	36
Extension Period Analysis	Withdrawal by Subject	4	5
Proof of Concept	Adverse Event	1	1
Proof of Concept	Physician Decision	1	0
Proof of Concept	Protocol Deviation	0	1
Proof of Concept	Study Termination by Sponsor	0	1
Proof of Concept	Withdrawal by Subject	0	4

Baseline characteristics

Characteristic	RO70123520 360 or 810 mg/Dose	Total	PoC Placebo to Extension Period Analysis RO7123520
Age, Continuous	53.4 Years STANDARD_DEVIATION 12.8	53.7 Years STANDARD_DEVIATION 12.9	54.7 Years STANDARD_DEVIATION 14.1
Ethnicity (NIH/OMB) Hispanic or Latino	73 Participants	81 Participants	27 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	18 Participants	28 Participants	10 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	16 Participants	16 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	2 Participants	2 Participants	2 Participants
Race (NIH/OMB) More than one race	4 Participants	6 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	3 Participants	5 Participants	0 Participants
Race (NIH/OMB) White	68 Participants	75 Participants	7 Participants
Sex: Female, Male Female	66 Participants	93 Participants	32 Participants
Sex: Female, Male Male	10 Participants	13 Participants	3 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	0 / 37	0 / 70	0 / 9	0 / 97
other Total, other adverse events	10 / 37	10 / 70	6 / 9	17 / 97
serious Total, serious adverse events	1 / 37	1 / 70	1 / 9	0 / 97

Outcome results

Primary

Change From Baseline in Bone Mineral Density Lumbar Spine L1-L4 as Assessed by Dual Energy X-ray Absorptiometry (DEXA) Scans

Time frame: Baseline, Week 12 of PoC and Week 12 of Extension Period Analysis (overall study week 24)

Population: The safety population included all participants who received at least one dose of study medication.

Arm	Measure	Group	Value (MEAN)	Dispersion
Placebo	Change From Baseline in Bone Mineral Density Lumbar Spine L1-L4 as Assessed by Dual Energy X-ray Absorptiometry (DEXA) Scans	Baseline	1.02 g/cm^2	Standard Deviation 0.21
Placebo	Change From Baseline in Bone Mineral Density Lumbar Spine L1-L4 as Assessed by Dual Energy X-ray Absorptiometry (DEXA) Scans	Week 12	-0.06 g/cm^2	Standard Deviation 0.2
Proof of Concept: RO7123520 810mg/Dose	Change From Baseline in Bone Mineral Density Lumbar Spine L1-L4 as Assessed by Dual Energy X-ray Absorptiometry (DEXA) Scans	Week 12	0.71 g/cm^2	Standard Deviation 5.5
Proof of Concept: RO7123520 810mg/Dose	Change From Baseline in Bone Mineral Density Lumbar Spine L1-L4 as Assessed by Dual Energy X-ray Absorptiometry (DEXA) Scans	Baseline	2.51 g/cm^2	Standard Deviation 12.46
Extension Period Analysis: RO7123520 360mg/Dose	Change From Baseline in Bone Mineral Density Lumbar Spine L1-L4 as Assessed by Dual Energy X-ray Absorptiometry (DEXA) Scans	Baseline	1.17 g/cm^2	Standard Deviation 0.2
Extension Period Analysis: RO7123520 360mg/Dose	Change From Baseline in Bone Mineral Density Lumbar Spine L1-L4 as Assessed by Dual Energy X-ray Absorptiometry (DEXA) Scans	Week 12	-0.01 g/cm^2	Standard Deviation 0.04
Extension Period Analysis: RO70123520 810mg/Dose	Change From Baseline in Bone Mineral Density Lumbar Spine L1-L4 as Assessed by Dual Energy X-ray Absorptiometry (DEXA) Scans	Baseline	2.06 g/cm^2	Standard Deviation 10.53
Extension Period Analysis: RO70123520 810mg/Dose	Change From Baseline in Bone Mineral Density Lumbar Spine L1-L4 as Assessed by Dual Energy X-ray Absorptiometry (DEXA) Scans	Week 12	0.58 g/cm^2	Standard Deviation 4.98

Primary

Percentage of Participants With Adverse Events

An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.

Time frame: Baseline to last participant last visit (approximately 2 years)

Population: The safety population included all participants who received at least one dose of study medication.

Arm	Measure	Value (NUMBER)
Placebo	Percentage of Participants With Adverse Events	48.6 Percentage of Participants
Proof of Concept: RO7123520 810mg/Dose	Percentage of Participants With Adverse Events	60.0 Percentage of Participants
Extension Period Analysis: RO7123520 360mg/Dose	Percentage of Participants With Adverse Events	66.7 Percentage of Participants
Extension Period Analysis: RO70123520 810mg/Dose	Percentage of Participants With Adverse Events	60.8 Percentage of Participants

Primary

Percentage of Participants With Anti-Drug Antibodies

Time frame: Baseline

Population: This outcome measure only includes the immunogenicity population, which was the PoC 810 mg dose group. These participants had at least 1 pre-dose ADA assessment.

Arm	Measure	Value (NUMBER)
Placebo	Percentage of Participants With Anti-Drug Antibodies	0 Percent

Primary

Proportion of Participants Achieving an American College of Rheumatology (ACR) 50 Response at Week 12

The ACR50 is a composite measure defined as both improvement of 50% in the number of tender and number of swollen joints, and a 50% improvement in three of the following five criteria: patient global assessment, physician global assessment, functional ability measure \[most often Health Assessment Questionnaire (HAQ)\], visual analog pain scale, and erythrocyte sedimentation rate or C-reactive protein (CRP). The ACR is reported as percent improvement at discrete time points.

Time frame: Week 12 of PoC and Week 12 of Extension Period Analysis (overall study week 24)

Population: The efficacy population included all randomized participants. Overall study = up to 32 weeks per participant. PoC = Weeks 1-12, Extension Period Analysis = Weeks 1-20 (overall study weeks 13-32)

Arm	Measure	Value (NUMBER)
Placebo	Proportion of Participants Achieving an American College of Rheumatology (ACR) 50 Response at Week 12	16.2 Percent
Proof of Concept: RO7123520 810mg/Dose	Proportion of Participants Achieving an American College of Rheumatology (ACR) 50 Response at Week 12	11.1 Percent
Extension Period Analysis: RO7123520 360mg/Dose	Proportion of Participants Achieving an American College of Rheumatology (ACR) 50 Response at Week 12	0 Percent
Extension Period Analysis: RO70123520 810mg/Dose	Proportion of Participants Achieving an American College of Rheumatology (ACR) 50 Response at Week 12	1.0 Percent

Secondary

Change From Baseline in Clinical Disease Activity Index (CDAI) Score at Week 12

The CDAI for Rheumatoid Arthritis (RA) assesses the severity of the disease using clinical data. It consists of the Patient Global disease Activity (PGA) estimate and the Evaluator Global disease Activity (EGA) estimate, each of which represent assessments of disease activity on a scale of 1-10, with 10 being maximum activity.

Time frame: Baseline, Week 12 of PoC and Week 12 of Extension Period Analysis (overall study week 24)